Valentino, Pamela L.

ABSTRACT Background The Society of Pediatric Liver Transplantation (SPLIT) has undergone tremendous growth with > 45 sites contributing data focusing on improving outcomes in pediatric liver transplantation (LT). We report and compare outcomes from the SPLIT Registry. Methods Patients < 18 years with first‐time LT only enrolled into the SPLIT Registry between 2011 and 2023 were included. Data was stratified into eras from the last published registry update (era 1: 2011–2018, era 2: 2018–2023). Results Three thousand five hundred four participants from 47 centers were included (era 1: n = 2159; era 2: n = 1345). Age distribution differed with more children < 1 year. of age at LT in era 2 (era 1: 29% vs. era 2: 33%, p = 0.01). Indications for LT were similar, with biliary atresia (38.8%) and metabolic disease (16.0%) being most common. Exception point use was higher in era 2 (era 1: 45% vs. era 2: 56%, p < 0.001). No difference in graft type (deceased: 81% era 1 vs. 78% era 2, p = 0.78), patient survival at 90 days (era 1: 98.7% vs. era 2: 98.3%), 1 year (era 1: 97.2 vs. era 2: 96.8%), or 3 years (era 1: 95.3% vs. era 2: 95.2%) was noted. Rate of hepatic artery thrombosis was lower in era 2 (era 1: 7% vs. era 2: 5%, p = 0.02). Conclusions Trends in pediatric LT within SPLIT note similar LT indications and graft type, higher utilization of exception points, and lower HAT rates despite transplanting more children < 10 kg. This data underscores the evolution of pediatric LT toward higher survivability and overall patient outcomes.

Background and Aims Recurrent primary sclerosing cholangitis (rPSC) following liver transplant (LT) has a negative impact on graft and patient survival; little is known about risk factors for rPSC or disease course in children. Approach and Results We retrospectively evaluated risk factors for rPSC in 140 children from the Pediatric PSC Consortium, a multicenter international registry. Recipients underwent LT for PSC and had >90 days of follow‐up. The primary outcome, rPSC, was defined using Graziadei criteria. Median follow‐up after LT was 3 years (interquartile range 1.1‐6.1). rPSC occurred in 36 children, representing 10% and 27% of the subjects at 2 years and 5 years following LT, respectively. Subjects with rPSC were younger at LT (12.9 vs. 16.2 years), had faster progression from PSC diagnosis to LT (2.5 vs. 4.1 years), and had higher alanine aminotransferase (112 vs. 66 IU/L) at LT (all P < 0.01). Inflammatory bowel disease was more prevalent in the rPSC group (86% vs. 66%; P = 0.025). After LT, rPSC subjects had more episodes of biopsy‐proved acute rejection (mean 3 vs. 1; P < 0.001), and higher prevalence of steroid‐refractory rejection (41% vs. 20%; P = 0.04). In those with rPSC, 43% developed complications of portal hypertension, were relisted for LT, or died within 2 years of the diagnosis. Mortality was higher in the rPSC group (11.1% vs. 2.9%; P = 0.05). Conclusions The incidence of rPSC in this cohort was higher than previously reported, and was associated with increased morbidity and mortality. Patients with rPSC appeared to have a more aggressive, immune‐reactive phenotype. These findings underscore the need to understand the immune mechanisms of rPSC, to lay the foundation for developing new therapies and improve outcomes in this challenging population.

Background and Aims Many children with primary sclerosing cholangitis (PSC) receive oral vancomycin therapy (OVT) or ursodeoxycholic acid (UDCA). There is a paucity of data on whether these medications improve outcomes. Approach and Results We analyzed retrospective data from the Pediatric PSC Consortium. Children treated with OVT were matched 1:1:1 to those treated with UDCA or managed with observation (no treatment) based on the closest propensity score, ensuring similar baseline characteristics. Two hundred sixty‐four patients (88 each with OVT, UDCA, or observation) had matching propensity scores and were similar in demographics, phenotype, immunosuppression, baseline biochemistry, and hepatic fibrosis. After 1 year in an intention‐to‐treat analysis, all outcome metrics were similar regardless of treatment group. In OVT, UDCA, and untreated groups, respectively: Gamma‐glutamyltransferase normalized in 53%, 49%, and 52% (P = not significant [NS]), liver fibrosis stage was improved in 20%, 13%, and 18% and worsened in 11%, 29%, and 18% (P = NS), and the 5‐year probability of liver transplant listing was 21%, 10%, and 12% (P = NS). Favorable outcome was associated with having a mild phenotype of PSC and minimal hepatic fibrosis. Conclusions We presented the largest‐ever description of outcomes on OVT in PSC and compared them to carefully matched patients on UDCA or no therapy. Neither OVT nor UDCA showed improvement in outcomes compared to a strategy of observation. Patients progressed to end‐stage liver disease at similar rates. Spontaneous normalization of biochemistry is common in children receiving no therapy, particularly in the majority of children with a mild phenotype and an early stage of disease. Placebo‐controlled treatment trials are needed to identify effective treatments for pediatric PSC.

Surgical innovation and multidisciplinary management have allowed children born with univentricular physiology congenital heart disease to survive into adulthood. An estimated global population of 70 000 patients have undergone the Fontan procedure and are alive today, most of whom are <25 years of age. Several unexpected consequences of the Fontan circulation include Fontan-associated liver disease. Surveillance biopsies have demonstrated that virtually 100% of these patients develop clinically silent fibrosis by adolescence. As they mature, there are increasing reports of combined heart-liver transplantation resulting from advanced liver disease, including bridging fibrosis, cirrhosis, and hepatocellular carcinoma, in this population. In the absence of a transplantation option, these young patients face a poor quality of life and overall survival. Acknowledging that there are no consensus guidelines for diagnosing and monitoring Fontan-associated liver disease or when to consider heart transplantation versus combined heart-liver transplantation in these patients, a multidisciplinary working group reviewed the literature surrounding Fontan-associated liver disease, with a specific focus on considerations for transplantation.

Background. In December 2018, United Network for Organ Sharing approved an allocation scheme based on recipients’ geographic distance from a deceased donor (acuity circles [ACs]). Previous analyses suggested that ACs would reduce waitlist mortality overall, but their impact on pediatric subgroups was not considered. Methods. We applied Scientific Registry of Transplant Recipients data from 2011 to 2016 toward the Liver Simulated Allocation Model to compare outcomes by age and illness severity for the United Network for Organ Sharing–approved AC and the existing donor service area–/region-based allocation schemes. Means from each allocation scheme were compared using matched-pairs t tests. Results. During a 3-year period, AC allocation is projected to decrease waitlist deaths in infants (39 versus 55; P < 0.001), children (32 versus 50; P < 0.001), and teenagers (15 versus 25; P < 0.001). AC allocation would increase the number of transplants in infants (707 versus 560; P < 0.001), children (677 versus 547; P < 0.001), and teenagers (404 versus 248; P < 0.001). AC allocation led to decreased median pediatric end-stage liver disease/model for end-stage liver disease at transplant for infants (29 versus 30; P = 0.01), children (26 versus 29; P < 0.001), and teenagers (26 versus 31; P < 0.001). Additionally, AC allocation would lead to fewer transplants in status 1B in children (97 versus 103; P = 0.006) but not infants or teenagers. With AC allocation, 77% of pediatric donor organs would be allocated to pediatric candidates, compared to only 46% in donor service area–/region-based allocation (P < 0.001). Conclusions. AC allocation will likely address disparities for pediatric liver transplant candidates and recipients by increasing transplants and decreasing waitlist mortality. It is more consistent with federally mandated requirements for organ allocation.

ABSTRACTBackground:Natural history models for primary sclerosing cholangitis (PSC) are derived from adult patient data, but have never been validated in children. It is unclear how accurate such models are for children with PSC.Methods:We utilized the pediatric PSC consortium database to assess the Revised Mayo Clinic, Amsterdam‐Oxford, and Boberg models. We calculated the risk stratum and predicted survival for each patient within each model using patient data at PSC diagnosis, and compared it with observed survival. We evaluated model fit using the c‐statistic.Results:Model fit was good at 1 year (c‐statistics 0.93, 0.87, 0.82) and fair at 10 years (0.78, 0.75, 0.69) in the Mayo, Boberg, and Amsterdam‐Oxford models, respectively. The Mayo model correctly classified most children as low risk, whereas the Amsterdam‐Oxford model incorrectly classified most as high risk. All of the models underestimated survival of patients classified as high risk. Albumin, bilirubin, AST, and platelets were most associated with outcomes. Autoimmune hepatitis was more prevalent in higher risk groups, and over‐weighting of AST in these patients accounted for the observed versus predicted survival discrepancy.Conclusions:All 3 models offered good short‐term discrimination of outcomes but only fair long‐term discrimination. None of the models account for the high prevalence of features of autoimmune hepatitis overlap in children and the associated elevated aminotransferases. A pediatric‐specific model is needed. AST, bilirubin, albumin, and platelets will be important predictors, but must be weighted to account for the unique features of PSC in children.

Adverse clinical events in primary sclerosing cholangitis (PSC) happen too slowly to capture during clinical trials. Surrogate endpoints are needed, but no such validated endpoints exist for children with PSC. We evaluated the association between gamma glutamyltransferase (GGT) reduction and long‐term outcomes in pediatric PSC patients. We evaluated GGT normalization (< 50 IU/L) at 1 year among a multicenter cohort of children with PSC who did or did not receive treatment with ursodeoxycholic acid (UDCA). We compared rates of event‐free survival (no portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or liver‐related death) at 5 years. Of the 287 children, mean age of 11.4 years old, UDCA was used in 81% at a mean dose of 17 mg/kg/day. Treated and untreated groups had similar GGT at diagnosis (314 versus 300, P= not significant [NS]). The mean GGT was reduced at 1 year in both groups, with lower values seen in treated (versus untreated) patients (99 versus 175, P= 0.002), but 5‐year event‐free survival was similar (74% versus 77%, P= NS). In patients with GGT normalization (versus no normalization) by 1 year, regardless of UDCA treatment status, 5‐year event‐free survival was better (91% versus 67%, P< 0.001). Similarly, larger reduction in GGT over 1 year (> 75% versus < 25% reduction) was also associated with improved outcome (5‐year event‐free survival 88% versus 61%, P= 0.005). Conclusion:A GGT < 50 and/or GGT reduction of > 75% by 1 year after PSC diagnosis predicts favorable 5‐year outcomes in children. GGT has promise as a potential surrogate endpoint in future clinical trials for pediatric PSC.

There are limited data on the natural history of primary sclerosing cholangitis (PSC) in children. We aimed to describe the disease characteristics and long‐term outcomes of pediatric PSC. We retrospectively collected all pediatric PSC cases from 36 participating institutions and conducted a survival analysis from the date of PSC diagnosis to dates of diagnosis of portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or death. We analyzed patients grouped by disease phenotype and laboratory studies at diagnosis to identify objective predictors of long‐term outcome. We identified 781 patients, median age 12 years, with 4,277 person‐years of follow‐up; 33% with autoimmune hepatitis, 76% with inflammatory bowel disease, and 13% with small duct PSC. Portal hypertensive and biliary complications developed in 38% and 25%, respectively, after 10 years of disease. Once these complications developed, median survival with native liver was 2.8 and 3.5 years, respectively. Cholangiocarcinoma occurred in 1%. Overall event‐free survival was 70% at 5 years and 53% at 10 years. Patient groups with the most elevated total bilirubin, gamma‐glutamyltransferase, and aspartate aminotransferase‐to‐platelet ratio index at diagnosis had the worst outcomes. In multivariate analysis PSC–inflammatory bowel disease and small duct phenotypes were associated with favorable prognosis (hazard ratios 0.6, 95% confidence interval 0.5‐0.9, and 0.7, 95% confidence interval 0.5‐0.96, respectively). Age, gender, and autoimmune hepatitis overlap did not impact long‐term outcome. Conclusion: PSC has a chronic, progressive course in children, and nearly half of patients develop an adverse liver outcome after 10 years of disease; elevations in bilirubin, gamma‐glutamyltransferase, and aspartate aminotransferase‐to‐platelet ratio index at diagnosis can identify patients at highest risk; small duct PSC and PSC–inflammatory bowel disease are more favorable disease phenotypes. (Hepatology 2017;66:518–527).