George V. Mazariegos

Portal Hypertension in Children: Expert Pediatric Opinion on the Report of the Baveno V Consensus Workshop on Methodology of Diagnosis and Therapy in Portal Hypertension

Shneider BL, Bosch J, de Franchis R, Emre SH, Groszmann RJ, Ling SC, Lorenz JM, Squires RH, Superina RA, Thompson AE, Mazariegos GV. Portal Hypertension in Children: Expert Pediatric Opinion on the Report of the Baveno V Consensus Workshop on Methodology of Diagnosis and Therapy in Portal Hypertension.

Health-Related Quality of Life and Family Function Following Pediatric Liver Transplantation

This multicenter study compared health‐related quality of life (HRQOL) and family function of pediatric liver transplant recipients to those of healthy children to determine if this population differed from a healthy population and to distinguish which pretransplant and posttransplant factors impact HRQOL and family function. HRQOL data from 102 patients achieving 2‐year survival were collected with the Infant Toddler Quality of Life Instrument or the Child Health Questionnaire Parent Form 50 parent surveys. Family functioning was assessed with the Family Assessment Device (FAD) completed by each participants family members. Demographic and clinical information were retrieved from the Studies of Pediatric Liver Transplant database. Recipients 5 years of age and older scored lower than a normative sample in physical health (P < 0.001), general health (P < 0.001), parental emotional impact (P < 0.001), and disruption of family activities (P < 0.001). Younger children, 2 to 5 years of age, scored lower than controls in global health (P = 0.004) and general health perceptions (P < 0.001) but did not differ in subscales measuring physical and psychosocial outcomes. Univariate analysis among the subscales identified demographic but not clinical variables as significant predictors of HRQOL. Mean scores of FAD scales were below published thresholds indicating healthy family functioning. As reported in previous studies, parents of older recipients reported higher levels of stress, although their level of family function appears normal. Significant associations were also observed between FAD scores and demographic variables, suggesting that further investigation of the impact of race, parental marital status, and socio‐economic status on the patient rehabilitation process is needed. Liver Transpl 14:460–468, 2008.

Liver Transplantation in Children with Cystic Fibrosis: A Long-Term Longitudinal Review of a Single Center's Experience

BACKGROUND Improved long-term survival in cystic fibrosis (CF) has led to an increased incidence of extrapulmonary complications of this disease. Of these, end-stage liver disease is a significant cause of morbidity and mortality with liver transplantation being the only effective therapy. METHODS Records of all CF pediatric liver transplant recipients were reviewed. RESULTS Twelve children with CF were the recipients of 16 allografts. The 1- and 5-year survival was 91.6% and 75%, respectively. There were 5 deaths at a mean interval of 6.8 +/- 6.3 years. All of these deaths were related to pulmonary disease. Pulmonary function improved or remained stable in 8 of 9 patients tested. Despite an 83% incidence of positive sputum cultures, there was only one early mortality related to pulmonary sepsis in the setting of primary liver allograft nonfunction. CONCLUSIONS Liver transplantation is acceptable treatment for children with CF and end-stage liver disease. Long-term survival is comparable to liver transplantation performed for other indications. Although posttransplant morbidity and mortality is related to lung disease, the authors speculate that as therapeutic improvements prolong the survival in CF, it is expected that longer survival after liver transplantation in this patient population may also be anticipated.

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.

Noncompliance after pediatric liver transplantation.

There were 34 episodes of documented noncompliance among 28 patients (15 males, 13 females) transplanted between March 1984 and May 1993. The mean age at the time of transplantation was 9 years (range, 2.6 to 16 years). The first episode of noncompliance was diagnosed at a mean age of 14.8 years (range, 10 to 20 years), and a mean of 6.5 years (range, 1.4 to 11.9 years) after transplantation. In those cases in which there was more than one episode of noncompliance, the mean time from the first to the second episode was 2.1 years (range, 0.6 to 3.9 years). At the time of noncompliance, 11 patients were on cyclosporine A (CyA) and 17 were receiving FK 506 (9 of which had been previously converted from CyA). There was a mean of 2.19 (range 0 to 6) episodes of rejection per patient before the diagnosis of noncompliance. Seventy-nine percent (n 5 22) of the noncompliant children had a history of psychiatric/ psychosocial associated factors. Liver biopsy specimens obtained at the time of noncompliance in 18 patients showed acute cellular rejection (n 5 8), hepatitis (n 5 5), hepatitis/rejection (n 5 3), and pericholangitis (n 5 2). Twenty-two patients had reinstitution of their baseline immunosuppressive drugs, FK 506 (n 5 17), and CyA (n 5 5). The remaining six were converted from CyA to FK 506. Four grafts were lost to chronic rejection, and one to rupture of a hepatic artery aneurysm after successful treatment of rejection. Three patients required retransplantation, one of them twice. There were two recurrences of noncompliance after retransplantation. Two patients died, the patient with the ruptured aneurysm and one of the retransplanted patients secondary to chronic rejection.

Allospecific CD154+ T cells identify rejection-prone recipients after pediatric small-bowel transplantation.

BACKGROUND Up to 70% of children with small bowel transplantation (SBTx) experience acute cellular rejection (ACR). Allospecific CD154+ T cells predict liver ACR in children in a novel, 16-hour mixed leukocyte response (MLR) assay, but remain untested in SBTx. METHODS The expression of CD154 was measured in 4 subsets-naive (N) and memory (M) CD154+ T-helper (Th) and T-cytotoxic (Tc) cells (ie, CD154+ ThN, CD154+ ThM, CD154+ TcN, and CD154+ TcM, respectively)-in the MLR of single blood samples obtained from 32 children with SBTx within 60 days of SBTx biopsy. Children showing ACR in these biopsies were termed Rejectors. The ratio of donor-induced to third-party-induced CD154+ T cells was called the immunoreactivity index (IR). We hypothesized that IR >1 denoted increased donor-specific alloreactivity and increased risk of rejection; in contrast, IR <1 implied decreased risk. CD154 expression was correlated with the expression of CTLA4, a negative T-cell costimulator that antagonizes and is inversely related to CD154 (n = 18). RESULTS Rejectors showed significantly greater numbers of donor-specific CD154+ T-cell subsets. Logistic regression analysis and leave-one-out cross validation followed by receiver operating characteristic analysis showed that, among the 4 subsets, IR > or =1.23 for CD154+ TcM identified Rejectors with a sensitivity and specificity of 93% and 88%. Also, a significant negative correlation was observed between CD154 expression and CTLA4 expression in allospecific Tc (Spearmans rho = -0.616, P = .006) but not in Th. CONCLUSION Allospecific CD154+ TcM identify rejection-prone children with SBTx.

Primary Prophylaxis of Variceal Bleeding in Children and the Role of MesoRex Bypass–Summary of the Baveno VI Pediatric Satellite Symposium

Approaches to the management of portal hypertension and variceal hemorrhage in pediatrics remain controversial, in large part because they are not well informed by rigorous clinical studies. Fundamental biological and clinical differences preclude automatic application of approaches used for adults to children. On April 11‐12, 2015, experts in the field convened at the first Baveno Pediatric Satellite Meeting to discuss and explore current available evidence regarding indications for MesoRex bypass (MRB) in extrahepatic portal vein obstruction and the role of primary prophylaxis of variceal hemorrhage in children. Consensus was reached regarding MRB. The vast majority of children with extrahepatic portal vein obstruction will experience complications that can be prevented by successful MRB surgery. Therefore, children with extrahepatic portal vein obstruction should be offered MRB for primary and secondary prophylaxis of variceal bleeding and other complications, if appropriate surgical expertise is available, if preoperative and intraoperative evaluation demonstrates favorable anatomy, and if appropriate multidisciplinary care is available for postoperative evaluation and management of shunt thrombosis or stenosis. In contrast, consensus was not achieved regarding primary prophylaxis of varices. Although variceal hemorrhage is a concerning complication of portal hypertension in children, the first bleed appears to be only rarely fatal and the associated morbidity has not been well characterized. Conclusion: There are few pediatric data to indicate the efficacy and safety of pharmacologic or endoscopic therapies as primary prophylaxis or that prevention of a sentinel variceal bleed will ultimately improve survival; therefore, no recommendation for primary prophylaxis with endoscopic variceal ligation, sclerotherapy, or nonspecific beta‐blockade in children was proposed. (Hepatology 2016;63:1368–1380)

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

Increased expression of peripheral blood leukocyte genes implicate CD14+ tissue macrophages in cellular intestine allograft rejection.

Recurrent rejection shortens graft survival after intestinal transplantation (ITx) in children, most of whom also experience early acute cellular rejection (rejectors). To elucidate mechanisms common to early and recurrent rejection, we used a test cohort of 20 recipients to test the hypothesis that candidate peripheral blood leukocyte genes that trigger rejection episodes would be evident late after ITx during quiescent periods in genome-wide gene expression analysis and would achieve quantitative real-time PCR replication pre-ITx (another quiescent period) and in the early post-ITx period during first rejection episodes. Eight genes were significantly up-regulated among rejectors in the late post-ITx and pre-ITx periods, compared with nonrejectors: TBX21, CCL5, GNLY, SLAMF7, TGFBR3, NKG7, SYNE1, and GK5. Only CCL5 was also up-regulated in the early post-ITx period. Among resting peripheral blood leukocyte subsets in randomly sampled nonrejectors, CD14(+) monocytes expressed the CCL5 protein maximally. Compared with nonrejectors, rejectors demonstrated higher counts of both circulating CCL5(+)CD14(+) monocytes and intragraft CD14(+) monocyte-derived macrophages in immunohistochemistry of postperfusion and early post-ITx biopsies from the test and an independent replication cohort. Donor-specific alloreactivity measured with CD154(+) T-cytotoxic memory cells correlated with the CCL5 gene and intragraft CD14(+) monocyte-derived macrophages at graft reperfusion and early post-ITx. CCL5 gene up-regulation and CD14(+) macrophages likely prime cellular ITx rejection. Infiltration of reperfused intestine allografts with CD14(+) macrophages may predict rejection events.

Liver and intestinal transplantation in a child with cystic fibrosis: a case report.

Abstract: Cystic fibrosis (CF) is an inherited disorder that presents as a multisystem disease with meconium ileus being the presenting symptom in 20% of patients. Approximately half of these patients present with complicated meconium ileus mandating early surgical intervention, potentially resulting in short gut syndrome. Although liver transplantation in children with CF has been described, this is the first report of a combined liver and small bowel transplant in a recipient with CF. A 7‐month‐old boy with CF presented with short bowel syndrome following extensive small bowel resection for meconium ileus and progressive cholestatic liver failure from intravenous hyperalimentation. He underwent combined liver and small intestinal transplant. He was discharged home three weeks post‐transplant on enteral feeds with supplemental intravenous fluid. He has had routine protocol small bowel allograft biopsies with no documented rejection episodes. He has been treated for minor respiratory infections without major sequelae. Improvements in pulmonary therapy have impacted on the survival in the CF population to the point where the need for multiorgan transplantation will be increased in the future. Extrapolating from the excellent experience of liver transplantation in children with CF, early liver and small intestinal multivisceral transplantation, if indicated, can be performed safely in children with CF.