Rene Romero

Studies of Pediatric Liver Transplantation (SPLIT) : Year 2000 outcomes

Background. Initiated in 1995, the Studies of Pediatric Liver Transplantation (SPLIT) registry database is a cooperative research network of pediatric transplantation centers in the United States and Canada. The primary objectives are to characterize and follow trends in transplant indications, transplantation techniques, and outcomes (e.g., patient/graft survival, rejection, growth parameters, and immunosuppressive therapy.) Methods. As of June 15, 2000, 29 centers registered 1144 patients, 640 of whom received their first liver-only transplant while registered in SPLIT. Patients are followed every 6 months for 2 years and yearly thereafter. Data are submitted to a central coordinating center. Results. One/two-year patient survival and graft loss estimates are 0.85/0.82 and 0.77/0.72, respectively. Risk factors for death include: in ICU at transplant (relative risk (RR)=2.63, P <0.05) and height/weight deficits of two or more standard deviations (RR=1.67, P <0.05). Risk factors for graft loss include: in ICU at transplant (RR=1.77, P <0.05) and receiving a cadaveric split organ compared with a whole organ (RR=2.3, P <0.05). The percentage of patients diagnosed with hepatic a. and portal v. thrombosis were 9.7% and 7%, respectively; 15% had biliary complications within 30 days. At least one re-operation was required in 45%. One/two-year rejection probability estimates are 0.60/0.66. Tacrolimus, as primary therapy posttransplant, reduces first rejection risk (RR=0.70, P <0.05). Eighty-nine percent of school-aged children are in school full-time, 18 months posttransplant. Conclusions. This report provides one of the first descriptions of characteristics and clinical courses of a multicenter pediatric transplant population. Observations are subject to patient selection biases but are useful for generating hypothesis for future studies.

Features of portal hypertension are associated with major adverse events in Fontan patients: The VAST study

BACKGROUND Chronic congestive hepatopathy is known to cause hepatic fibrosis and portal hypertension in patients post-Fontan operation for single ventricle palliation. The clinical significance of these findings is not clear. We hypothesized that features of portal hypertension would be significantly related to major adverse events. METHODS A retrospective review of 73 adult and pediatric post-Fontan patients referred for a liver evaluation from 2001 to 2011 was performed. The relationship between features of portal hypertension (VAST score ≥2, 1 point each for Varices, Ascites, Splenomegaly or Thrombocytopenia) and a major adverse event (death, need for transplant, or hepatocellular carcinoma) was examined using logistic regression. RESULTS 73 post-Fontan patients (30% female, 73% Caucasian, 66% systemic left ventricle (SLV), mean age 24±11 years, mean interval from Fontan 17±6 years) were included in analysis. Features of portal hypertension (VAST score ≥2) were present in 26 (36%), and there were 19 major adverse events: death (n=12), transplant (n=6), and HCC (n=1). A significant relationship was found between VAST score ≥2 and major adverse events (OR=9.8, 95% CI [2.9-32.7]). After adjusting for time since Fontan, SLV, age, hemoglobin and type of failure, VAST score ≥2 remained significant (OR=9.1, 95% CI [1.4-57.6]). CONCLUSION Fontan patients with features of portal hypertension have a 9-fold increased risk for a major adverse event. Therapies targeted to manage clinical manifestations of portal hypertension, and early referral to heart transplant may help delay major adverse events. Future prospective studies are needed to confirm these findings.

Intravenous N-acetylcysteine in pediatric patients with nonacetaminophen acute liver failure: A placebo-controlled clinical trial

N‐acetylcysteine (NAC) was found to improve transplantation‐free survival in only those adults with nonacetaminophen (non‐APAP) acute liver failure (ALF) and grade 1‐2 hepatic encephalopathy (HE). Because non‐APAP ALF differs significantly between children and adults, the Pediatric Acute Liver Failure (PALF) Study Group evaluated NAC in non‐APAP PALF. Children from birth through age 17 years with non‐APAP ALF enrolled in the PALF registry were eligible to enter an adaptively allocated, doubly masked, placebo‐controlled trial using a continuous intravenous infusion of NAC (150 mg/kg/day in 5% dextrose in water [D5W]) or placebo (D5W) for up to 7 days. The primary outcome was 1‐year survival. Secondary outcomes included liver transplantation‐free survival, liver transplantation (LTx), length of intensive care unit (ICU) and hospital stays, organ system failure, and maximum HE score. A total of 184 participants were enrolled in the trial with 92 in each arm. The 1‐year survival did not differ significantly (P = 0.19) between the NAC (73%) and placebo (82%) treatment groups. The 1‐year LTx‐free survival was significantly lower (P = 0.03) in those who received NAC (35%) than those who received placebo (53%), particularly, but not significantly so, among those less than 2 years old with HE grade 0‐1 (NAC 25%; placebo 60%; P = 0.0493). There were no significant differences between treatment arms for hospital or ICU length of stay, organ systems failing, or highest recorded grade of HE. Conclusion: NAC did not improve 1‐year survival in non‐APAP PALF. One‐year LTx‐free survival was significantly lower with NAC, particularly among those <2 years old. These results do not support broad use of NAC in non‐APAP PALF and emphasizes the importance of conducting controlled pediatric drug trials, regardless of results in adults. (HEPATOLOGY 2013)

Use of Corticosteroids After Hepatoportoenterostomy for Bile Drainage in Infants With Biliary Atresia: The START Randomized Clinical Trial

IMPORTANCE Biliary atresia is the most common cause of end-stage liver disease in children. Controversy exists as to whether use of steroids after hepatoportoenterostomy improves clinical outcome. OBJECTIVE To determine whether the addition of high-dose corticosteroids after hepatoportoenterostomy is superior to surgery alone in improving biliary drainage and survival with the native liver. DESIGN, SETTING, AND PATIENTS The multicenter, double-blind Steroids in Biliary Atresia Randomized Trial (START) was conducted in 140 infants (mean age, 2.3 months) between September 2005 and February 2011 in the United States; follow-up ended in January 2013. INTERVENTIONS Participants were randomized to receive intravenous methylprednisolone (4 mg/kg/d for 2 weeks) and oral prednisolone (2 mg/kg/d for 2 weeks) followed by a tapering protocol for 9 weeks (n = 70) or placebo (n = 70) initiated within 72 hours of hepatoportoenterostomy. MAIN OUTCOMES AND MEASURES The primary end point (powered to detect a 25% absolute treatment difference) was the percentage of participants with a serum total bilirubin level of less than 1.5 mg/dL with his/her native liver at 6 months posthepatoportoenterostomy. Secondary outcomes included survival with native liver at 24 months of age and serious adverse events. RESULTS The proportion of participants with improved bile drainage was not statistically significantly improved by steroids at 6 months posthepatoportoenterostomy (58.6% [41/70] of steroids group vs 48.6% [34/70] of placebo group; adjusted relative risk, 1.14 [95% CI, 0.83 to 1.57]; P = .43). The adjusted absolute risk difference was 8.7% (95% CI, -10.4% to 27.7%). Transplant-free survival was 58.7% in the steroids group vs 59.4% in the placebo group (adjusted hazard ratio, 1.0 [95% CI, 0.6 to 1.8]; P = .99) at 24 months of age. The percentage of participants with serious adverse events was 81.4% [57/70] of the steroids group and 80.0% [56/70] of the placebo group (P > .99); however, participants receiving steroids had an earlier time of onset of their first serious adverse event by 30 days posthepatoportoenterostomy (37.2% [95% CI, 26.9% to 50.0%] of steroids group vs 19.0% [95% CI, 11.5% to 30.4%] of placebo group; P = .008). CONCLUSIONS AND RELEVANCE Among infants with biliary atresia who have undergone hepatoportoenterostomy, high-dose steroid therapy following surgery did not result in statistically significant treatment differences in bile drainage at 6 months, although a small clinical benefit could not be excluded. Steroid treatment was associated with earlier onset of serious adverse events in children with biliary atresia. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00294684.

Extrahepatic Anomalies in Infants With Biliary Atresia: Results of a Large Prospective North American Multicenter Study

The etiology of biliary atresia (BA) is unknown. Given that patterns of anomalies might provide etiopathogenetic clues, we used data from the North American Childhood Liver Disease Research and Education Network to analyze patterns of anomalies in infants with BA. In all, 289 infants who were enrolled in the prospective database prior to surgery at any of 15 participating centers were evaluated. Group 1 was nonsyndromic, isolated BA (without major malformations) (n = 242, 84%), Group 2 was BA and at least one malformation considered major as defined by the National Birth Defects Prevention Study but without laterality defects (n = 17, 6%). Group 3 was syndromic, with laterality defects (n = 30, 10%). In the population as a whole, anomalies (either major or minor) were most prevalent in the cardiovascular (16%) and gastrointestinal (14%) systems. Group 3 patients accounted for the majority of subjects with cardiac, gastrointestinal, and splenic anomalies. Group 2 subjects also frequently displayed cardiovascular (71%) and gastrointestinal (24%) anomalies; interestingly, this group had genitourinary anomalies more frequently (47%) compared to Group 3 subjects (10%). Conclusion: This study identified a group of BA (Group 2) that differed from the classical syndromic and nonsyndromic groups and that was defined by multiple malformations without laterality defects. Careful phenotyping of the patterns of anomalies may be critical to the interpretation of both genetic and environmental risk factors associated with BA, allowing new insight into pathogenesis and/or outcome. (Hepatology 2013;58:1724–1731)

Evaluation of the pediatric patient for liver transplantation: 2014 practice guideline by the american association for the study of liver diseases, american society of transplantation and the north american society for pediatric gastroenterology, hepatology and nutrition

Current American Association for the Study of Liver Diseases (AASLD) liver transplant evaluation guidelines include both adult and pediatric patients. While pediatric liver transplants account for 7.8% of all liver transplants in the United States, sufficient differences between pediatric and adult patients seeking liver transplantation (LT) now require independent, yet complementary documents. This document will focus on pediatric issues at each level of the evaluation process. Disease categories suitable for referral to a pediatric LT program are similar to adults: acute liver failure, autoimmune, cholestasis, metabolic or genetic, oncologic, vascular, and infectious. However, specific etiologies and outcomes differ widely from adult patients, justifying independent pediatric guidelines. Data supporting our recommendations are based on a Medline search of the English language literature from 1997 to the present. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the available evidence supporting the recommendations, the AASLD Practice Guidelines Committee has adopted the classification used by the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) workgroup with minor modifications (Table 1). The classifications and recommendations are based on three categories: the source of evidence in levels I through III; the Abbreviations: ALF, acute liver failure; GRADE, Grading of Recommendation Assessment, Development, and Evaluation; HB, hepatoblastoma; HCC, hepatocellular carcinoma; HPE, hepatoportoenterostomy; LT, liver transplantation; OTPN, Organ Procurement and Transplantation Network; PFIC, progressive familial intrahepatic cholestasis; TIPS, transjugular intrahepatic portosystemic shunt. From the Department of Pediatrics, University of Pittsburgh School of Medicine; Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA; Department of Pediatrics, University of Toronto; Division of Pediatric Gastroenterology, Hepatology and Nutrition, SickKids Transplant and Regenerative Medicine Center, Hospital for Sick Children, Toronto, Canada; Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Emory University School of Medicine; Children’s Healthcare of Atlanta, Atlanta, GA; Department of Pediatrics, Division of Pediatric Gastroenterology and Hepatology, Yale School of Medicine, New Haven, CT; Department of Paediatrics, University of Melbourne; Department of Gastroenterology, Royal Children’s Hospital, Melbourne, Australia; Department of Surgery, Section of Transplantation and Immunology, Yale School of Medicine, New Haven, CT; Department of Surgery, University of Pittsburgh School of Medicine; Division of Pediatric Transplantation, Hillman Center for Pediatric Transplantation, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA. Financial support to develop this practice guideline was provided by the American Association for the Study of Liver Diseases. All AASLD Practice Guidelines are updated annually. If you are viewing a Practice Guideline that is more than 12 months old, please visit www.aasld.org for an update in the material. Received April 22, 2014; accepted April 22, 2014. Address reprint requests to: Robert H. Squires, M.D., Professor of Pediatrics, University of Pittsburgh, Children’s Hospital of Pittsburgh of UPMC, 4401 Penn Ave., Pittsburgh, PA 15224. E-mail: squiresr@upmc.edu Copyright VC 2014 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27191 Potential conflict of interest: Dr. Romero received grants from Bristol-Myers Squibb.

Pediatric liver transplantation with daclizumab induction therapy

Background. A new class of monoclonal antibodies (non-T–cell depleting) has gained favor for induction therapy after transplantation. This study evaluated the non-T–cell depleting antibody to the CD25 cell, daclizumab, as a single-dose induction agent immediately after pediatric liver transplantation to spare the use of the calcineurin inhibitor, tacrolimus, for 7 days in respect to both efficacy and renal function. Methods. From January 1998 to November 2001, 81 pediatric orthotopic liver transplant recipients receiving 89 liver grafts were evaluated. The treatment arm (n=61) received daclizumab 1 mg/kg immediately after liver transplantation along with mycophenolate, steroids, and, on postoperative day 7, tacrolimus. The control group did not receive induction therapy, whereas tacrolimus, mycophenolate, and steroids were started immediately after surgery. Results. The induction group had fewer patients with rejection within the first 30 days after liver transplantation (9 [14.8%] vs. 10 [50%]; P =0.003). The mean time to first rejection was similar between groups (12.1 [±7.8] days vs. 18.5 [±8.1] days; P =not significant). There was a 3.39 increase in relative risk to develop rejection within the first 30 days after orthotopic liver transplantation if the patient did not receive induction therapy (relative risk=3.39; 95% confidence interval [1.61, 7.14]). Two-year actuarial survival for the induction group was 93.2% compared with 85% in the control; graft survival was also similar between groups (87.8% vs. 72.7%) at 2 years. Conclusion. Daclizumab 1 mg/kg given immediately after pediatric liver transplantation and withholding tacrolimus, is safe, efficacious, and reduces rejections within the first 30 days after surgery.

Successful ABO-incompatible pediatric liver transplantation utilizing standard immunosuppression with selective postoperative plasmapheresis

Transplanting blood group A, B, or O (ABO)‐incompatible (ABO‐I) liver grafts has resulted in lower patient and graft survival with an increased incidence of vascular and biliary complications and rejection. We report that, without modification of our standard immunosuppression protocol, crossing blood groups is an acceptable option for children requiring liver transplantation. In our study, ABO‐I liver grafts—regardless of recipient age—have comparable long‐term survival (mean follow‐up of 3.25 yr) with ABO‐compatible grafts without any difference in rejection, vascular or biliary complications. From January 1, 1999 to October 1, 2005, we studied 138 liver transplants in 121 children: 16 (13.2%) received an ABO incompatible liver allograft. One‐year actuarial patient survival for ABO‐matched grafts vs. ABO‐I grafts was 93.0% and 100%, respectively, whereas graft survival was 83.4% and 92.3%. Additionally, 6 of 16 (37.5%) ABO‐I transplanted children had 8 rejection episodes, whereas 47 patients (44.8%) had 121 rejection episodes in the ABO‐compatible group. There were no vascular complications and 2 biliary strictures in the ABO‐I group. Plasmapheresis was not used for pretransplantation desensitization and was only required in 1 posttransplantation recipient. No child was splenectomized. Six of the 16 children were older than 13 yr of age, suggesting the possibility of successfully expanding this technique to an older population. In conclusion, our outcomes may support the concept of using ABO‐I grafts in a more elective setting associated with split and living donor liver transplants. Liver Transpl 12:972–978, 2006.

Associations among genotype, clinical phenotype, and intracellular localization of trafficking proteins in ARC syndrome

Arthrogryposis–renal dysfunction–cholestasis (ARC) syndrome is a rare autosomal recessive multisystem disorder caused by mutations in vacuolar protein sorting 33 homologue B (VPS33B) and VPS33B interacting protein, apical–basolateral polarity regulator (VIPAR). Cardinal features of ARC include congenital joint contractures, renal tubular dysfunction, cholestasis, severe failure to thrive, ichthyosis, and a defect in platelet alpha‐granule biogenesis. Most patients with ARC do not survive past the first year of life. We report two patients presenting with a mild ARC phenotype, now 5.5 and 3.5 years old. Both patients were compound heterozygotes with the novel VPS33B donor splice‐site mutation c.1225+5G>C in common. Immunoblotting and complementary DNA analysis suggest expression of a shorter VPS33B transcript, and cell‐based assays show that c.1225+5G>C VPS33B mutant retains some ability to interact with VIPAR (and thus partial wild‐type function). This study provides the first evidence of genotype–phenotype correlation in ARC and suggests that VPS33B c.1225+5G>C mutation predicts a mild ARC phenotype. We have established an interactive online database for ARC (https://grenada.lumc.nl/LOVD2/ARC) comprising all known variants in VPS33B and VIPAR. Also included in the database are 15 novel pathogenic variants in VPS33B and five in VIPAR. Hum Mutat 33:1656–1664, 2012.

Hepatic artery thrombosis in pediatric liver transplantation

PURPOSE Children have been reported to be at greater risk for hepatic artery thrombosis when compared to adults due to small arterial size, nonuse of intraoperative microscope, and postoperative hypercoagulable state. METHODS We evaluated arterial anastomosis type, intraoperative field magnification, and hepatic artery complications and how they were managed. All patients underwent ultrasound, anticoagulation consisted of 41 mg aspirin once a day, and 35 patients received alprostadil (PGE) for the first 7 days after transplantation. No patients were administered intravenous heparin following liver transplantation. RESULTS Of the 74 livers transplanted, 36 grafts (48.6%) were whole organ transplants and 38 grafts (51.4%) were partial livers. We observed HAT in 1 of 74 (1.35%) transplants in our pediatric liver transplant population. The only patient with HAT was a young girl with a history of biliary atresia. The occurrence of a hepatic artery thrombosis on day 7 was caused by the migration of an intimal plaque dissection within the artery graft. She was emergently taken back into the operating room for graft revision. This individual currently has a survival time of 426 days following her last transplant. CONCLUSIONS Hepatic artery thrombosis may be minimized in pediatric liver transplantation without the use of microsurgery. Anticoagulation utilizing ASA and alprostadil is sufficient to avoid HAT. Accurate use of ultrasound is crucial to avoid this complication. Graft and patient salvage is possible with expedient surgical treatment; microsurgery, anticoagulant therapy, site of arterial inflow, and recipient size and weight.