Udeme D. Ekong

Complete Immunosuppression Withdrawal and Subsequent Allograft Function Among Pediatric Recipients of Parental Living Donor Liver Transplants

CONTEXT Although life-saving, liver transplantation burdens children with lifelong immunosuppression and substantial potential for morbidity and mortality. OBJECTIVE To establish the feasibility of immunosuppression withdrawal in pediatric living donor liver transplant recipients. DESIGN, SETTING, AND PATIENTS Prospective, multicenter, open-label, single-group pilot trial conducted in 20 stable pediatric recipients (11 male; 55%) of parental living donor liver transplants for diseases other than viral hepatitis or an autoimmune disease who underwent immunosuppression withdrawal. Their median age was 6.9 months (interquartile range [IQR], 5.5-9.1 months) at transplant and 8 years 6 months (IQR, 6 years 5 months to 10 years 9 months) at study enrollment. Additional entry requirements included stable allograft function while taking a single immunosuppressive drug and no evidence of acute or chronic rejection or significant fibrosis on liver biopsy. Gradual immunosuppression withdrawal over a minimum of 36 weeks was instituted at 1 of 3 transplant centers between June 5, 2006, and November 18, 2009. Recipients were followed up for a median of 32.9 months (IQR, 1.0-49.9 months). MAIN OUTCOME MEASURES The primary end point was the proportion of operationally tolerant patients, defined as patients who remained off immunosuppression therapy for at least 1 year with normal graft function. Secondary clinical end points included the durability of operational tolerance, and the incidence, timing, severity, and reversibility of rejection. RESULTS Of 20 pediatric patients, 12 (60%; 95% CI, 36.1%-80.9%) met the primary end point, maintaining normal allograft function for a median of 35.7 months (IQR, 28.1-39.7 months) after discontinuing immunosuppression therapy. Follow-up biopsies obtained more than 2 years after completing withdrawal showed no significant change compared with baseline biopsies. Eight patients did not meet the primary end point secondary to an exclusion criteria violation (n = 1), acute rejection (n = 2), or indeterminate rejection (n = 5). Seven patients were treated with increased or reinitiation of immunosuppression therapy; all returned to baseline allograft function. Patients with operational tolerance compared with patients without operational tolerance initiated immunosuppression withdrawal later after transplantation (median of 100.6 months [IQR, 71.8-123.5] vs 73.0 months [IQR, 57.6-74.9], respectively; P = .03), had less portal inflammation (91.7% [95% CI, 61.5%-99.8%] vs 42.9% [95% CI, 9.9%-81.6%] with no inflammation; P = .04), and had lower total C4d scores on the screening liver biopsy (median of 6.1 [IQR, 5.1-9.3] vs 12.5 [IQR, 9.3-16.8]; P = .03). CONCLUSION In this pilot study, 60% of pediatric recipients of parental living donor liver transplants remained off immunosuppression therapy for at least 1 year with normal graft function and stable allograft histology.

Graft histology characteristics in long‐term survivors of pediatric liver transplantation

The factors that influence the long‐term histological outcome of transplanted liver allografts in children are not yet fully understood, and the role of surveillance biopsies in patients with normal graft function remains controversial. The aims of this study were to describe the long‐term graft histology of pediatric liver transplant recipients surviving at least 3 years and to analyze factors correlating with long‐term histological outcome. Histological slides of 63 long‐term liver transplant recipients were assessed for inflammation and fibrosis. The histological findings were correlated with clinical, biochemical, serological, and radiological findings. A significant proportion of biopsies from these patients showed some type of histological abnormalities, with fibrosis being observed in 61 (97%) patients. Duration of transplantation of >6 years and ≥grade 2 inflammation were significantly associated with advanced fibrosis. We could not identify any correlation between ≥stage 3 fibrosis and donor age, cold and warm ischemia time, history of de novo autoimmune hepatitis, hepatic artery thrombosis, chronic rejection, or alanine aminotransferase, aspartate aminotransferase, and gamma‐glutamyl transferase values. In conclusion, liver fibrosis appears to be a common finding in long‐term pediatric liver transplant survivors. The cause of this fibrosis is uncertain, and normal alanine aminotransferase, aspartate aminotransferase, and gamma‐glutamyl transferase levels do not exclude the presence of significant fibrosis. Liver Transpl 14:1582–1587, 2008.

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.

Neonatal hemochromatosis: fetal liver disease leading to liver failure in the fetus and newborn.

Abstract:  Acute liver failure in the newborn is relatively rare but often fatal. The broadest definition of acute liver failure is failure of the vital functions of the liver occurring within weeks or a few months of the onset of clinical liver disease. Therefore, by definition, any liver failure in the newborn can be construed to be acute liver failure. A second component of the general definition of acute liver failure is the lack of known preexisting liver disease. In the case of neonatal acute liver failure, preexisting disease would by definition be liver disease that affects the fetus. Almost nothing is known about fetal onset liver failure, and there is no literature addressing the subject. This review will address fetal liver disease that leads to liver failure in the fetus or newborn.

Guideline for the Evaluation of Cholestatic Jaundice in Infants: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

ABSTRACT Cholestatic jaundice in infancy affects approximately 1 in every 2500 term infants and is infrequently recognized by primary providers in the setting of physiologic jaundice. Cholestatic jaundice is always pathologic and indicates hepatobiliary dysfunction. Early detection by the primary care physician and timely referrals to the pediatric gastroenterologist/hepatologist are important contributors to optimal treatment and prognosis. The most common causes of cholestatic jaundice in the first months of life are biliary atresia (25%–40%) followed by an expanding list of monogenic disorders (25%), along with many unknown or multifactorial (eg, parenteral nutrition-related) causes, each of which may have time-sensitive and distinct treatment plans. Thus, these guidelines can have an essential role for the evaluation of neonatal cholestasis to optimize care. The recommendations from this clinical practice guideline are based upon review and analysis of published literature and the combined experience of the authors. The committee recommends that any infant noted to be jaundiced after 2 weeks of age be evaluated for cholestasis with measurement of total and direct serum bilirubin, and that an elevated serum direct bilirubin level (direct bilirubin levels >1.0 mg/dL or >17 &mgr;mol/L) warrants timely consideration for evaluation and referral to a pediatric gastroenterologist or hepatologist. Of note, current differential diagnostic plans now incorporate consideration of modern broad-based next-generation DNA sequencing technologies in the proper clinical context. These recommendations are a general guideline and are not intended as a substitute for clinical judgment or as a protocol for the care of all infants with cholestasis. Broad implementation of these recommendations is expected to reduce the time to the diagnosis of pediatric liver diseases, including biliary atresia, leading to improved outcomes.

Disparate Clinical Presentation of Neonatal Hemochromatosis in Twins

Neonatal hemochromatosis (NH) is a rare disease of gestation that results in fetal liver injury and extrahepatic siderosis. The etiology of NH is not fully understood. However, the rate of recurrence of NH in the pregnancy after an affected one is ∼80%. A spectrum of liver disease has been recognized, spanning from liver failure in the fetus or neonate to infants that survive with medical therapy. Here we report on 2 sets of fraternal twins, each set with a gross disparity in the severity of presentation: 1 infant with liver failure and the other nearly unaffected. These findings suggest a need to look carefully for subclinical disease in the siblings of patients with NH by using sensitive tests such as those for ferritin and α-fetoprotein. They also suggest that affected infants may be missed when using routine clinical testing, which would lead to the apparent rate of recurrence, understating the actual recurrence rate.

Paediatric hepatocellular carcinoma due to somatic CTNNB1 and NFE2L2 mutations in the setting of inherited bi-allelic ABCB11 mutations

Hepatocellular carcinoma (HCC) rarely occurs in childhood. We describe a patient with new onset of pruritus at 8 months of age who at 17 months of age was found to have a 2.5 cm HCC. To delineate the possible genetic basis of this tumour, we performed whole exome sequencing (WES) of the germline DNA and identified two novel predictably deleterious missense mutations in ABCB11, encoding bile salt export pump (BSEP), confirmed in the parental DNA as bi-allelic and inherited. Although inherited ABCB11 mutations have previously been linked to HCC in a small number of cases, the molecular mechanisms of hepatocellular carcinogenesis in ABCB11 disease are unknown. WES of the HCC tissue uncovered somatic driver mutations in the beta-catenin (CTNNB1) and nuclear-factor-erythroid-2-related-factor-2 (NFE2L2) genes. Moreover, clonality analysis predicted that the CTNNB1 mutation was clonal and occurred earlier during carcinogenesis, whereas the NFE2L2 mutation was acquired later. Interestingly, background liver parenchyma showed no inflammation or fibrosis and BSEP expression was preserved. This is the first study to identify somatic CTNNB1 and NFE2L2 mutations in early childhood arisen in the setting of inherited bi-allelic ABCB11 mutations. Rapid WES analysis expedited this childs diagnosis and treatment, and likely improved her prognosis.

The SPLIT research agenda 2013.

This review focuses on active clinical research in pediatric liver transplantation with special emphasis on areas that could benefit from studies utilizing the SPLIT infrastructure and data repository. Ideas were solicited by members of the SPLIT Research Committee and sections were drafted by members of the committee with expertise in those given areas. This review is intended to highlight priorities for clinical research that could successfully be conducted through the SPLIT collaborative and would have significant impact in pediatric liver transplantation.

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.

Received April 30, 2014; From the Department of and Nutrition, SickKid Division of Pediatric Division of Pediatric G of Melbourne, Melbou Haven, CT, and the # Address correspondence a UPMC, 4401 Penn A This guideline is copubli Supplemental digital cont text of this article on This practice guideline wa which provided peer Liaison), Hari S. Con Merriman, MD, Geral MD, and Helen S. Ye Guidelines Committe Hepatology, and Nutri guideline was provide R.R. has received grants The other authors report Copyright # 2014 by Gastroenterology, He DOI: 10.1097/MPG.0000

Liver Transplantation Followed by Allogeneic Hematopoietic Stem Cell Transplantation for Atypical Mevalonic Aciduria

Mevalonic aciduria because of mutations of the gene for mevalonate kinase causes limited synthesis of isoprenoids, the effects of which are widespread. The outcome for affected children is poor. A child with severe multisystem manifestations underwent orthotopic liver transplantation at age 50 months for the indication of end‐stage liver disease. This procedure corrected liver function and eliminated portal hypertension, and the patient showed substantial improvement in neurological function. However, autoinflammatory episodes continued unabated until hematopoietic stem cell transplantation was performed at 80 months. Through this complex therapy, the patient now enjoys a high quality of life without significant disability.