Amy G. Feldman

Clues to the etiology of bile duct injury in biliary atresia.

Biliary atresia (BA) is an infantile obstructive cholangiopathy of unknown etiology with suboptimal therapy, which is responsible for 40 to 50% of all pediatric liver transplants. Although the etiology of bile duct injury in BA in unknown, it is postulated that a pre- or perinatal viral infection initiates cholangiocyte apoptosis and release of antigens that trigger a Th1 immune response that leads to further bile duct injury, inflammation, and obstructive fibrosis. Humoral immunity and activation of the innate immune system may also play key roles in this process. Moreover, recent investigations from the murine BA model and human data suggest that regulatory T cells and genetic susceptibility factors may orchestrate autoimmune mechanisms. What controls the coordination of these events, why the disease only occurs in the first few months of life, and why a minority of infants with perinatal viral infections develop BA are remaining questions to be answered.

Biliary atresia: cellular dynamics and immune dysregulation

The cause of biliary atresia is unknown; in the past few decades, the majority of investigations related to its pathogenesis have centered on viral infections and immunity. The acquired or perinatal form of biliary atresia entails a progressive inflammatory injury of bile ducts, leading to fibrosis and obliteration of both the extrahepatic and intrahepatic bile ducts. Theories of pathogenesis include viral infection, chronic inflammatory or autoimmune-mediated bile duct injury, and abnormalities in bile duct development. This review will focus solely on human studies pertaining to a potential viral trigger of bile duct injury at diagnosis and provide insight into the interplay of the innate and adaptive immune responses in the pathogenesis of disease.

Regulatory T cells inhibit Th1 cell-mediated bile duct injury in murine biliary atresia

BACKGROUND & AIMS Biliary atresia (BA) is a pediatric inflammatory disease of the biliary system which leads to cirrhosis and the need for liver transplantation. One theory regarding etiology is that bile duct injury is due to virus-induced autoreactive T cell-mediated inflammation. Regulatory T cell (Treg) abnormalities in BA could result in unchecked bystander inflammation and autoimmunity targeting bile ducts. The aim of this study was to determine if Tregs are dysfunctional in the rotavirus-induced mouse model of BA (murine BA). METHODS Murine BA resulted from infection of BALB/c neonates with Rhesus rotavirus (RRV). RESULTS Liver Tregs from BA mice were decreased in number, activation marker expression, and suppressive function. Adoptive transfer studies revealed that RRV-infected mice that received Tregs had significantly increased survival (84%) compared to controls (12.5%). In addition, ablation of Tregs in older mice, followed by RRV infection, resulted in increased bile duct injury. CONCLUSIONS These studies demonstrate that dysregulation of Tregs is present in murine BA and that diminished Treg function may be implicated in the pathogenesis of human BA.

Biliary atresia: Indications and timing of liver transplantation and optimization of pretransplant care

Biliary atresia (BA) is a progressive, fibro‐obliterative disorder of the intrahepatic and extrahepatic bile ducts in infancy. The majority of affected children will eventually develop end‐stage liver disease and require liver transplantation (LT). Indications for LT in BA include failed Kasai portoenterostomy, significant and recalcitrant malnutrition, recurrent cholangitis, and the progressive manifestations of portal hypertension. Extrahepatic complications of this disease, such as hepatopulmonary syndrome and portopulmonary hypertension, are also indications for LT. Optimal pretransplant management of these potentially life‐threatening complications and maximizing nutrition and growth require the expertise of a multidisciplinary team with experience caring for BA. The timing of transplant for BA requires careful consideration of the potential risk of transplant versus the survival benefit at any given stage of disease. Children with BA often experience long wait times for transplant unless exception points are granted to reflect severity of disease. Family preparedness for this arduous process is therefore critical. Liver Transplantation 23:96–109 2017 AASLD.

B Cell Deficient Mice Are Protected from Biliary Obstruction in the Rotavirus-Induced Mouse Model of Biliary Atresia

A leading theory regarding the pathogenesis of biliary atresia (BA) is that bile duct injury is initiated by a virus infection, followed by an autoimmune response targeting bile ducts. In experimental models of autoimmune diseases, B cells have been shown to play an important role. The aim of this study was to determine the role of B cells in the development of biliary obstruction in the Rhesus rotavirus (RRV)-induced mouse model of BA. Wild-type (WT) and B cell-deficient (Ig-α-/-) mice received RRV shortly after birth. Ig-α-/- RRV-infected mice had significantly increased disease-free survival rate compared to WT RRV-infected BA mice (76.8% vs. 17.5%). In stark contrast to the RRV-infected BA mice, the RRV-infected Ig-α-/- mice did not have hyperbilirubinemia or bile duct obstruction. The RRV-infected Ig-α-/- mice had significantly less liver inflammation and Th1 cytokine production compared to RRV-infected WT mice. In addition, Ig-α-/- mice had significantly increased numbers of regulatory T cells (Tregs) at baseline and after RRV infection compared to WT mice. However, depletion of Tregs in Ig-α-/- mice did not induce biliary obstruction, indicating that the expanded Tregs in the Ig-α-/- mice were not the sole reason for protection from disease. Conclusion: B cell deficient Ig-α-/- mice are protected from biliary obstruction in the RRV-induced mouse model of BA, indicating a primary role of B cells in mediating disease pathology. The mechanism of protection may involve lack of B cell antigen presentation, which impairs T-cell activation and Th1 inflammation. Immune modulators that inhibit B cell function may be a new strategy for treatment of BA.

Biliary Atresia: Clinical Lessons Learned.

ABSTRACT Biliary atresia is a rare disease of unclear etiology, in which obstruction of the biliary tree causes severe cholestasis leading to cirrhosis and ultimately death if left untreated. Biliary atresia is the leading cause of neonatal cholestasis and the most frequent indication for pediatric liver transplantation. Any infant with persistent jaundice beyond 2 weeks of life needs to be evaluated for biliary atresia with fractionation of the bilirubin into conjugated and unconjugated portions. Early performance of a hepatoportoenterostomy in the first 45 days of life to restore bile flow and lessen further damage to the liver is thought to optimize outcome. Despite surgery, progressive liver scarring occurs, and 80% of patients with biliary atresia will require liver transplantation during childhood.

Impaired physical function following pediatric LT.

The purpose of this article is to investigate the spectrum of physical function of pediatric liver transplantation (LT) recipients 12‐24 months after LT. Review data were collected through the functional outcomes group, an ancillary study of the Studies of Pediatric Liver Transplantation registry. Patients were eligible if they had survived LT by 12‐24 months. Children ≥ 8 years and parents completed the Pediatric Quality of Life Inventory™ 4.0 generic core scales, which includes 8 questions assessing physical function. Scores were compared to a matched healthy child population (n = 1658) and between survivors with optimal versus nonoptimal health. A total of 263 patients were included. Median age at transplant and survey was 4.8 years (interquartile range [IQR], 1.3‐11.4 years) and 5.9 years (IQR, 2.6‐13.1 years), respectively. The mean physical functioning score on child and parent reports were 81.2 ± 17.3 and 77.1 ± 23.7, respectively. Compared to a matched healthy population, transplant survivors and their parents reported lower physical function scores (P < 0.001); 32.9% of patients and 35.0% of parents reported a physical function score <75, which is > 1 standard deviation below the mean of a healthy population. Physical functioning scores were significantly higher in survivors with optimal health than those with nonoptimal health (P < 0.01). There was a significant relationship between emotional functioning and physical functioning scores for LT recipients (r = 0.69; P < 0.001). In multivariate analysis, primary disease, height z score < –1.64 at longterm follow‐up (LTF) visit,  > 4 days of hospitalization since LTF visit, and not being listed as status 1 were predictors of poor physical function. In conclusion, pediatric LT recipients 1‐2 years after LT and their parents report lower physical function than a healthy population. Findings suggest practitioners need to routinely assess physical function, and the development of rehabilitation programs may be important. Liver Transplantation 22 495‐504 2016 AASLD

Immunization practices among pediatric transplant hepatologists.

Vaccination of pediatric liver transplant candidates and recipients represents an opportunity to decrease infectious complications following transplant. Although vaccine recommendations exist, studies have shown that many transplant candidates and recipients are under‐immunized. The goals of this study were to assess among pediatric transplant hepatologists: (i) current immunization practices before and after transplantation, (ii) involvement of an ID physician in the transplant evaluation, and (iii) perceptions about vaccine safety and barriers to immunization. An 80‐item e‐mail survey of pediatric transplant hepatologists at centers in the United States and Canada participating in the SPLIT consortium was conducted from December 2014 to March 2015. The overall response rate was 80% (73/91), representing 97% (32/33) of SPLIT centers. Fifty percent of programs routinely involved an ID physician in the transplant evaluation. Administration of palivizumab was routinely considered by 48% of hepatologists pre‐transplant and by 41% post‐transplant. Live vaccines were recommended by 26% of hepatologists after transplant. About 10% of hepatologists reported concern that live vaccines after transplant could induce rejection. There is wide variation in immunization practices among transplant hepatologists. Specific evidence‐based protocols are needed to guide immunization practices in transplant candidates and recipients.

Hospitalizations for Respiratory Syncytial Virus and Vaccine-Preventable Infections in the First 2 Years After Pediatric Liver Transplant

Objectives To examine in liver transplant recipients at centers participating in the Pediatric Health Information System dataset the number of hospitalizations for respiratory syncytial virus (RSV) and vaccine‐preventable infections (VPIs) in the first 2 years after transplantation, morbidity and mortality associated with these hospitalizations, and costs associated with these hospitalizations. Study design A retrospective cohort study of patients <18 years of age who underwent liver transplantation at a Pediatric Health Information System center between January 1, 2004, and December 31, 2012. Hospitalizations for RSV/VPIs during the first 2 years post‐transplant were ascertained using International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. Data were collected on clinical care, outcomes, and costs during these hospitalizations. Results There were 2554 liver transplant recipients identified; 415 patients (16.3%) had 544 cases of RSV/VPIs. RSV, rotavirus, and influenza were the most common infections resulting in hospitalization. Ninety‐two patients (3.6%) had RSV/VPI during their transplant hospitalization. Transplant hospitalizations complicated by RSV/VPI were longer (44 days vs. 21 days; P < .001), had higher rejection rates (37% vs. 26%; P = .02), and were more expensive (

Neurodevelopmental Outcome of Young Children with Biliary Atresia and Native Liver: Results from the ChiLDReN Study

259 697 vs.