Patrick McKiernan

British paediatric surveillance unit study of biliary atresia: outcome at 13 years.

Background: Little information is available on contemporary, prospectively collected data on the long-term outcome of national cohorts of children with biliary atresia. Objective: This study aimed to describe the current outcome of a national cohort of children with biliary atresia. Patients and Methods: All 93 cases of biliary atresia in the United Kingdom and Ireland diagnosed between March 1993 and February 1995 were followed up prospectively. Results: A total of 91 children underwent Kasai portoenterostomy in 15 individual centres. Only 2 centres treated more than 5 children annually. Median age at last follow-up was 12 years (range 0.25–14). Fifteen children (16%) have died: 10 after unsuccessful portoenterostomy, 1 of sepsis after successful portoenterostomy, and 4 after liver transplantation. Forty-two (45%) underwent liver transplantation at a median age of 1 year (range 0.5–9), with 90% survival. All 41 children with failed portoenterostomy (and 2 without portoenterostomy) died or underwent liver transplantation at a median age of 0.8 years (range 0.25–6.5). When the portoenterostomy was successful, 40 of 50 patients (80%) are alive without liver transplantation. The 13-year actuarial survival without liver transplantation is 43.8% overall and is better in children treated at centres that treat more than 5 cases yearly (54% vs 27.3%, P = 0.005). Conclusions: If the portoenterostomy is successful, then few children with biliary atresia will need transplantation before adolescence. Children with biliary atresia should be treated in experienced centres to maximize the chance of successful surgery.

Late Graft Hepatitis and Fibrosis in Pediatric Liver Allograft Recipients : Current Concepts and Future Developments

Liver transplantation (LT) in children now has a 20‐year survival of >80%, but the longterm outcome of these grafts remains uncertain. Serial protocol liver biopsies after transplantation from several pediatric centres have demonstrated the gradual development of unexplained graft inflammation (“idiopathic” posttransplant hepatitis; IPTH) and graft fibrosis in biopsies obtained >12 months post‐LT in children with good graft function and (near) normal liver biochemistry. Although the clinical significance of these findings is uncertain, there is evidence to suggest that IPTH may be a form of rejection or chronic antibody‐mediated rejection as it is associated with the presence of auto/alloantibodies; de novo Class II donor‐specific HLA antibodies (DSA); previous episodes of rejection, and may improve or be prevented with increased immunosuppression. Currently, the only method of diagnosing either hepatitis or fibrosis has been by serial protocol biopsies as neither serum markers of fibrosis nor noninvasive methods to detect fibrosis such as transient elastography (TE) are sufficiently validated in children. This review will focus on the diagnosis and management of idiopathic posttransplant hepatitis and graft fibrosis, discuss current methods for detecting graft injury, and potential mechanisms for their development. Liver Transplantation 22 1593–1602 2016 AASLD.

Sequencing of FIC1, BSEP and MDR3 in a large cohort of patients with cholestasis revealed a high number of different genetic variants

BACKGROUND & AIMSnThe bile salt export pump (BSEP, ABCB11), multidrug resistance protein 3 (MDR3, ABCB4) and the ATPase familial intrahepatic cholestasis 1 (FIC1, ATP8B1) mediate bile formation. This study aimed to determine the contribution of mutations and common variants in the FIC1, BSEP and MDR3 genes to cholestatic disorders of differing disease onset and severity.nnnMETHODSnCoding exons with flanking intron regions of ATP8B1, ABCB11, and ABCB4 were sequenced in cholestatic patients with assumed genetic cause. The effects of new variants were evaluated by bioinformatic tools and 3D protein modeling.nnnRESULTSnIn 427 patients with suspected inherited cholestasis, 149 patients carried at least one disease-causing mutation in FIC1, BSEP or MDR3, respectively. Overall, 154 different mutations were identified, of which 25 were novel. All 13 novel missense mutations were disease-causing according to bioinformatics analyses and homology modeling. Eighty-two percent of patients with at least one disease-causing mutation in either of the three genes were children. One or more common polymorphism(s) were found in FIC1 in 35.3%, BSEP in 64.3% and MDR3 in 72.6% of patients without disease-causing mutations in the respective gene. Minor allele frequencies of common polymorphisms in BSEP and MDR3 varied in our cohort compared to the general population, as described by gnomAD. However, differences in ethnic background may contribute to this effect.nnnCONCLUSIONSnIn a large cohort of patients, 154 different variants were detected in FIC1, BSEP, and MDR3, 25 of which were novel. In our cohort, frequencies for risk alleles of BSEP (p.V444A) and MDR3 (p.I237I) polymorphisms were significantly overrepresented in patients without disease-causing mutation in the respective gene, indicating that these common variants can contribute to a cholestatic phenotype.nnnLAY SUMMARYnFIC1, BSEP, and MDR3 represent hepatobiliary transport proteins essential for bile formation. Genetic variants in these transporters underlie a broad spectrum of cholestatic liver diseases. To confirm a genetic contribution to the patients phenotypes, gene sequencing of these three major cholestasis-related genes was performed in 427 patients and revealed 154 different variants of which 25 have not been previously reported in a database. In patients without a disease-causing mutation, common genetic variants were detected in a high number of cases, indicating that these common variants may contribute to cholestasis development.

Long-term outcomes of de novo autoimmune hepatitis in pediatric liver transplant recipients

The long‐term course and outcome of DAIH is unknown. A retrospective multicenter study assessing associations and long‐term consequences of DAIH developing in a transplanted allograft is presented. Children with DAIH were followed from diagnosis until death, re‐LT, or transfer of care and for a minimum of 1 year. A total of 31 patients of 1833 (1.7%) LT were identified; 29 followed for a median of 7.1 years (range, 1.6‐15); 52% had no rejection preceding diagnosis of DAIH. Transaminases fell following treatment with steroids and antimetabolites (ALT 108 vs 39 U/L (P=.002); AST 112 vs 52 U/L (P=.003); GGT 72 vs 36 U/L (P=.03), but this was not universally sustained. Transaminases >2X ULN observed in 38% of patients at last follow‐up; commonly GGT, attributed to bile duct injury and ductopenia. Portal hypertension (PHT) was seen in four patients and associated with severe fibrosis and cirrhosis. Re‐LT occurred in two patients for chronic rejection (CR) and uncontrolled PHT with gastrointestinal bleeding, respectively. No deaths from DAIH were reported. DAIH is an uncommon complication following pediatric LT requiring prolonged and augmented immunosuppression. It is associated with continued allograft dysfunction and may lead to bile duct injury, CR, and PHT necessitating re‐LT.

Liver Transplantation for Propionic Acidemia and Methylmalonic Acidemia: Perioperative Management and Clinical Outcomes

Propionic acidemia (PA) and methylmalonic acidemia (MMA) comprise the most common organic acidemias and account for profound morbidity in affected individuals. Although liver transplantation (LT) has emerged as a bulk enzyme‐replacement strategy to stabilize metabolically fragile patients, it is not a metabolic cure because patients remain at risk for disease‐related complications. We retrospectively studied LT and/or liver‐kidney transplant in 9 patients with PA or MMA with additional focus on the optimization of metabolic control and management in the perioperative period. Metabolic crises were common before transplant. By implementing a strategy of carbohydrate minimization with gradual but early lipid and protein introduction, lactate levels significantly improved over the perioperative period (P < 0.001). Posttransplant metabolic improvement is demonstrated by improvements in serum glycine levels (for PA; P < 0.001 × 10–14), methylmalonic acid levels (for MMA; P < 0.001), and ammonia levels (for PA and MMA; P < 0.001). Dietary restriction remained after transplant. However, no further metabolic crises have occurred. Other disease‐specific comorbidities such as renal dysfunction and cardiomyopathy stabilized and improved. In conclusion, transplant can provide a strategy for altering the natural history of PA and MMA providing stability to a rare but metabolically brittle population. Nutritional management is critical to optimize patient outcomes.