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Background: The objectives of this position statement were to provide evidence-based and expert-informed recommendations for exercise training in adult and children solid organ transplant (SOT) candidates and recipients and on the outcomes relevant to exercise training and physical function that should be evaluated in SOT., Methods: We identified randomized controlled trials (RCTs) and systematic reviews of exercise interventions in adult and pediatric SOT candidates and recipients. When RCTs were not available, studies of any design were reviewed. The key recommendations were based on scientific evidence and expert-informed opinion., Results: We recommended that exercise training should be offered in the pre- and posttransplant phase for both adults and children. In adults, exercise training pretransplant was safe, but there was insufficient evidence to provide specific guidelines on the training characteristics. RCTs in adult SOT recipients demonstrated that exercise training improved exercise capacity, lower extremity muscle strength, and health-related quality of life. To obtain benefits, exercise training should be of moderate to vigorous-intensity level, 3-5 times a week for a minimum of 8 weeks. In pediatrics, there is an urgent need for high-quality multicenter clinical trials in the pre- and posttransplant phases. Due to limited evidence, specific recommendations regarding training characteristics could not be provided for pediatrics., Conclusions: The clinical relevance of this position statement is that it provides a key step toward raising awareness of the importance of exercise training in SOT patients among transplant professionals. It also identifies key areas for further research.

Background: Passenger lymphocyte syndrome (PLS) is a less known etiology of acute onset anemia following ABO-compatible (ABO-c) liver transplantation (LT). Available literature on PLS after pediatric LT is limited. Therefore, we evaluated the prevalence, clinical course, and risk factors of PLS in children following ABO-c LT., Methods: A single-center retrospective review of all children who underwent LT between 2000 and 2017 was performed. PLS was defined as a drop-in hemoglobin >20 g/L within 30 days of LT, with positive direct antiglobulin test and 1 laboratory test confirming hemolysis. Chi square and student t tests compared variables between subjects with and without PLS., Results: Amongst 333 pediatric LT performed, 51 children received an ABO-c graft. PLS was diagnosed in 7 (14%) subjects at a median of 10 days after LT. There were no significant differences in patient demographics, graft type, or immunosuppression between those who did and did not develop PLS. Recipient blood group A+ receiving a donor O+ graft was a risk factor for PLS (P = 0.015). All PLS subjects recovered with blood transfusions (median 2), and no additional interventions. Three subjects initially received recipient (instead of donor) blood group red cells., Conclusions: We report a 14% prevalence of PLS following pediatric ABO-c LT. Recipient blood group A+ receiving a donor O+ graft is a risk factor for PLS. Recognition of PLS as a cause of early acute anemia in pediatric ABO-c LT enables timely transfusion with donor (rather than recipient) blood group red cells.

Objectives: MMA is associated with chronic tubulointerstitial nephritis and a progressive decline in GFR. Optimal management of these children is uncertain. Our objectives were to document the pre-, peri-, and post-transplant course of all children with MMA who underwent liver or combined liver-kidney transplant in our centers., Design and Methods: Retrospective chart review of all cases of MMA who underwent organ transplantation over the last 10 years., Results: Five children with MMA underwent liver transplant (4/5) and combined liver-kidney transplant (1/5). Three were Mut 0 and two had a cobalamin B disorder. Four of five were transplanted between ages 3 and 5 years. Renal dysfunction prior to transplant was seen in 2/5 patients. Post-transplant (one liver transplant and one combined transplant) renal function improved slightly when using creatinine-based GFR formula. We noticed in 2 patients a big discrepancy between creatinine- and cystatin C-based GFR calculations. One patient with no renal disease developed renal failure post-liver transplantation. Serum MMA levels have decreased in all to <300 μmol/L. Four patients remain on low protein diet, carnitine, coenzyme Q, and vitamin E post-transplant., Conclusions: MMA is a complex metabolic disorder. Renal disease can continue to progress post-liver transplant and close follow-up is warranted. More research is needed to clarify best screening GFR method in patients with MMA. Whether liver transplant alone, continued protein restriction, or the addition of antioxidants post-transplant can halt the progression of renal disease remains unclear., (© 2019 Wiley Periodicals, Inc.)

Objective: The primary goal in intestinal failure (IF) is adaptation and enteral autonomy (EA). Our goals were to determine the proportion of patients treated for IF by an established intestinal rehabilitation program who achieved EA and to assess the predictors of EA., Background: There have been considerable advancements in the management of IF over the last 15 years, children with short bowel syndrome with a reduction in mortality. Several studies have discussed variables that may influence the ability to attain EA; however, majority were written when mortality rates were considerably higher compared with the current contemporary experience., Methods: A retrospective analysis of infants <12 months with short bowel syndrome referred between 2006 and 2013 (n = 120). Data was collected on IF-related factors and nutritional intake. The cohort was stratified based on achievement of EA. Statistical testing completed using t test, Chi Square, and Cox Proportional Hazards regression (P < 0.05)., Results: EA was achieved in 84 (70.0%) patients. Patients who remained parenteral nutrition dependent were more likely to have volvulus (1.2 vs 22.2%, P < 0.001), shorter percent residual small bowel (29.4 vs 68.6%; P < 0.0001) and colon length (64.6 vs 86.0%; P = 0.001), and no ileocecal valve (61.1 vs 29.8%; P = 0.05). Mortality was also decreased in those who achieved EA (4 vs 22%; P = 0.004). Percent residual small bowel (HR = 1.03; 95% CI 1.02-1.03) and colon (HR = 1.01; 95% CI 1.00-1.02) length were positively associated with EA, while number of septic episodes was negatively associated (HR = 0.95; 95% CI 0.91-0.99)., Conclusion: Seventy percent of infants with IF achieved EA. Residual small and large bowel length were the most important predictors of EA and septic events had a negative impact.

Purpose: The serial transverse enteroplasty (STEP) tapers and lengthens the gut to improve adaptation. Mortality has decreased with multidisciplinary intestinal rehabilitation programs (IRP) allowing more time to reach adaptive potential. We reviewed our STEP experience to compare surgical outcomes between early and late eras of our IRP., Methods: A retrospective cohort study of all STEP patients managed by our IRP (Jan 2003-Dec 2016; era 1 2003-2005, era 2 2006-2016) was completed. Patient demographics, operative data, complications, and outcome data were collected. Univariate analysis between eras with nonparametric statistics was performed., Results: Thirty-six patients received STEP (Era 1 = 12; Era 2 = 24) [median age 5mo; males 22/36 (61.1%)]. In Era 2 a higher proportion had gastroschisis (8.3% vs 58.3%); p = 0.004) and shorter pre-STEP small bowel remnant (48 vs 111 cm, p = 0.001). The median increase in bowel length post-STEP was 52.9%. Overall, 42% of patients reached enteral autonomy (Era 1 7/12 (58%) vs Era 2 8/24 (33%); p = 0.15). Median time to PN discontinuation was shorter in Era 1 (259 vs 968 days, p = .208). Staple line complications were higher in Era 1 (16.7% vs 0%; p = 0.040)., Conclusion: Presently, STEP is reserved for a specific subset of IRP patients, allowing 42% to wean off PN. STEP's use should be under the umbrella of a multidisciplinary IRP., Type of Study: Retrospective cohort study., Level of Evidence: III., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Survival rates of infants with intestinal failure (IF) are increasing, yet multiple medical factors may impact development., Aims: This study examines neurodevelopmental outcomes at 12-15 and 26-32 months corrected age in a cohort of children with IF., Study Design: Prospective single centre neurodevelopmental assessments of children admitted to an intestinal rehabilitation program between 2011 and 2013. Outcome measures include: Mullen Scales of Early Learning (12 and 26 months), and Vineland-II Adaptive Behaviour Scales - Caregiver Report (26 months). Standard scores were correlated with medical and demographic factors., Results: Thirty-one children (17 males), median gestational age 34 weeks (IQR 30-36) with birth weight (BW) 2.12 kg (IQR 1.24-2.52). Ten (32.2%) were dependent on parental nutrition (PN) at the second assessment. At 12 months, 11/30 (36.7%) scored below average (>1SD below mean) on the early learning composite and 24/30 (80%) were below average on the gross motor subscale. Comparatively, at 26 months, mean early learning scores were significantly lower with >50% scoring below average. Mean gross motor scores remained low, and 14/27 (51.9%) were below average on the Vineland-II motor domain. At 12 months, factors significantly associated with lower scores are primarily related to prematurity. At 26 months, the impact of IF-related variables such as bowel length and PN days are more apparent., Conclusion: Children with IF are at risk of developmental delay in multiple domains. While gross motor skills appear to be most significantly affected, cognitive deficits become more apparent at 26 months, highlighting the importance of early developmental follow up., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Living donor liver transplantation (LDLT) is increasingly used to bridge the gap between the current supply and demand imbalance for deceased donor organs to provide lifesaving liver transplantation., Methods: Outcomes of 135 children who underwent LDLT were compared with 158 recipients of deceased donor liver transplantation (DDLT) at the largest pediatric liver transplant program in Canada., Results: Recipients of LDLT were significantly younger than deceased donor recipients ( P ≤ 0.001), less likely to require dialysis pretransplant ( P < 0.002) and had shorter wait time duration when the primary indication was cholestatic liver disease ( P = 0.003). The LDLT donors were either related genetically or emotionally (79%), or unrelated (21%) to the pediatric recipients. One-, 5-, and 10-year patient survival rates were significantly higher in LDLT (97%, 94%, and 94%) compared with DDLT (92%, 87%, and 80%; log-rank P = 0.02) recipients, as were graft survival rates (96%, 93%, and 93% for LDLT versus 89%, 81.4%, and 70%, respectively, for DDLT; log-rank P = 0.001). Medical and surgical complications were not statistically different between groups. Graft failure was higher in recipients of DDLT (odds ratio, 2.60; 95% confidence interval, 1.02, 6.58) than in the LDLT group after adjustment for clinical characteristics and propensity score., Conclusions: Living donor liver transplantation provides superior outcomes for children and is an excellent and effective strategy to increase the chances of receiving a liver transplant., Competing Interests: The authors declare no funding or conflicts of interest.

In recent years, the cross talk between the liver and the immune system is being uncovered, in part by studying liver involvement in primary immune deficiencies (PID) and in part by investigating the alterations of the immune system following orthotopic liver transplantation (OLT). Here we review some of the reciprocal interactions between the liver and the immune system. Patients with PID, particularly those involving inherited defects in T and B cells or innate immunity are prone to infections and inflammatory responses that often involve the liver. Omenn's syndrome, familial hemophagocytic lymphohistiocytosis, AIRE, FOXP3 and CD25 deficiencies, common variable immunodeficiency, CD40 ligand deficiency, chronic granulomatous disease and autoimmune lymphoproliferative syndrome are some of the notable PID associated with typical hepatobiliary abnormalities. Knowledge gained from studying these PID together with laboratory and histological evaluations can assist in managing PID-associated liver dysfunction. The liver itself also has important effects on the immune system, as evident from the growing experience with patients surviving OLT. Up to 40% of pediatric patients who receive OLT suffer from post transplantation allergy, autoimmunity, and immune-mediated disorders (PTAA). PTAA is more common after liver and heart transplantations than kidney transplantations. Potential contributing factors for the increased frequency of PTAA after OLT include the age of the patients, the prolonged use of tacrolimus and the reduced regulatory immune function with a shift towards a TH2 immune response. Better understanding of the mechanisms leading to the development of PTAA after OLT will also improve the management of these conditions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

De novo autoimmune hepatitis (DAIH) is an important cause of late allograft dysfunction following liver transplantation, but its cause and underlying pathogenesis remains unclear. We sought to identify specific innate and adaptive immune mechanisms driving the pro-inflammatory cytokine secreting regulatory T cell (Treg) phenotype in DAIH and determine if modulation of these pathways could resolve the inflammatory milieu observed in the livers of patients with DAIH. Here, we demonstrate toll-like receptors (TLRs) 2- and 4-mediated inflammasome activation in CD14 ++ monocytes, a finding that is key to maintaining dysfunctional Tregs in patients with DAIH. Furthermore, silencing of TLR 2 and 4 in CD14 ++ monocytes prevented activation of the inflammasome and significantly decreased IFN-γ production by FOXP3 + Tregs. We also observed significantly increase in expression of tumor necrosis factor α-induced protein 3 ( TNFAIP3 ), a negative regulator of the NLRP3 Inflammasome, in monocytes/macrophages of liver transplant subjects who have normal allograft function and do not have DAIH. TNFAIP3 expression was virtually absent in monocytes/macrophages of patients with DAIH. Our findings suggest that autoimmunity in DAIH is promoted by CD14 ++ monocytes predominantly through activation of inflammatory signaling pathways.

Diarrhea is common in infants (children less than 2 years of age), usually acute, and, if chronic, commonly caused by allergies and occasionally by infectious agents. Congenital diarrheas and enteropathies (CODEs) are rare causes of devastating chronic diarrhea in infants. Evaluation of CODEs is a lengthy process and infrequently leads to a clear diagnosis. However, genomic analyses and the development of model systems have increased our understanding of CODE pathogenesis. With these advances, a new diagnostic approach is needed. We propose a revised approach to determine causes of diarrhea in infants, including CODEs, based on stool analysis, histologic features, responses to dietary modifications, and genetic tests. After exclusion of common causes of diarrhea in infants, the evaluation proceeds through analyses of stool characteristics (watery, fatty, or bloody) and histologic features, such as the villus to crypt ratio in intestinal biopsies. Infants with CODEs resulting from defects in digestion, absorption, transport of nutrients and electrolytes, or enteroendocrine cell development or function have normal villi to crypt ratios; defects in enterocyte structure or immune-mediated conditions result in an abnormal villus to crypt ratios and morphology. Whole-exome and genome sequencing in the early stages of evaluation can reduce the time required for a definitive diagnosis of CODEs, or lead to identification of new variants associated with these enteropathies. The functional effects of gene mutations can be analyzed in model systems such as enteroids or induced pluripotent stem cells and are facilitated by recent advances in gene editing procedures. Characterization and investigation of new CODE disorders will improve management of patients and advance our understanding of epithelial cells and other cells in the intestinal mucosa., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objectives: To describe the prevalence, natural course, outcome, and risk factors of post-transplant de novo allergy and autoimmunity., Study Design: A cross-sectional, cohort study of all children (<18 years) who underwent a solid-organ transplantation, between 2000 and 2012, in a single transplant center, with a follow-up period of 6 months or more post-transplant and without history of allergy or immune-mediated disorder pretransplant., Results: A total of 626 eligible patients were screened, and 273 patients (160 males; 59%) met the inclusion criteria; this included 111 liver, 103 heart, 52 kidney, and 7 multivisceral recipients. Patients were followed for a median period of 3.6 years. A total of 92 (34%) patients (42 males, 46%) developed allergy or autoimmune disease after transplantation, with a high prevalence among liver (41%), heart (40%), and multivisceral (57%) transplant recipients compared with kidney recipients (4%; P < .001). Post-transplant allergies included eczema (n = 44), food allergy (22), eosinophilic gastrointestinal disease (11), and asthma (28). Autoimmunity occurred in 18 (6.6%) patients, presenting mainly as autoimmune cytopenia (n = 10). In a multivariate analysis, female sex, young age at transplantation, family history of allergy, Epstein-Barr virus infection, and elevated eosinophil count >6 months post-transplantation were associated with an increased risk for allergy or autoimmunity. Two patients (0.7%) died from autoimmune hemolytic anemia and hemophagocytic lymphohistiocytosis, and 52 episodes of post-transplant allergy, autoimmunity, and immune-mediated disorders (37%) did not improve over time., Conclusions: Allergy and autoimmunity are common in pediatric liver, heart, and multivisceral transplant recipients and pose a significant health burden. Further studies are required to clarify the mechanisms behind this post-transplant immune dysregulation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: The aim of the study was to describe long-term growth postpediatric liver transplantation and to conduct bivariate and multivariate analysis of factors that may predict post-transplantation growth in children who received a liver transplant from January 1999 to December 2008 at the Hospital for Sick Children., Methods: A retrospective cohort study was conducted with follow-up of up-to 10 years post-transplantation. Mean height and weight z scores and annual differences in mean z scores were plotted against time after transplantation. A 1-way analysis of variance was conducted. Multivariate and univariate Cox proportional hazards analyses were conducted to determine factors associated with reaching the 50th and 25th percentiles for height., Results: A total of 127 children met eligibility criteria. The mean height z score at time of transplantation was -2.21 which by the second year post-transplantation increased significantly to -0.66 (mean increase of 1.55 standard deviation units). There were no further significant increases in mean height z score from 2 years post-transplantation until the end of follow-up at year 10. In multivariate analysis, height at transplant was the most important predictor of linear growth post-transplantation., Conclusions: Children who underwent liver transplantation had significant catch-up growth in the first 2 years post-transplantation followed by a plateau phase. Increased height z-score at transplantation is the most important predictor of long-term growth.

Purpose of Review: Long-term outcomes in patients with intestinal failure and following intestine transplantation have improved significantly over the last decade. With these improvements, listing criteria for intestine transplantation are reevaluated and the role of quality of life (QoL) in patients' outcome is increasingly studied and emphasized. Here, we review the recent literature on QoL before and after intestine transplantation and discuss whether QoL should be considered as a listing criterion for intestine transplantation., Recent Findings: Patients on home parenteral nutrition, experience lower QoL compared with healthy population and equal or lower QoL than patients with other chronic diseases. After transplantation, QoL improves and is comparable in some QoL domains to that of the general population. These findings are limited by heterogeneous study designs and sample size. Although QoL improves after intestine transplantation, long-term survival of patients receiving HPN surpass postintestine transplantation survival. Poor QoL is not associated with an increased mortality in patients receiving HPN., Summary: Current survival outcomes of intestine transplantation do not justify poor QoL as a single listing criterion for intestine transplantation. However, intestine transplantation should be considered in patients with unique circumstances of extremely poor QoL. This approach may change once postintestine transplantation patient survival will further improve.

Lipid emulsions have been associated with liver injury. Newer mixed emulsions (ML), such as SMOFlipid (Fresenius Kabi, Germany), are thought to be more hepatoprotective than soybean-based emulsions (SL), such as Intralipid (Baxter). Pediatric studies comparing long-term use between the 2 are limited. This study compares the severity of hepatic injury between a prospective cohort of hospitalized children on ML (n = 20) and a historical age- and diagnosis-matched cohort of hospitalized children on SL (n = 20). Median exposure to ML and SL were 10 versus 6 weeks (P = 0.030), respectively, at similar median lipid doses (2.2 vs 2.1 g · kg · day). Using a generalized estimating equations approach, conjugated bilirubin trajectory was found to be lower in patients on ML compared with SL (P < 0.001), suggesting that prolonged exposure (≥4 weeks) to ML is associated with decreased liver injury compared with SL in hospitalized children.

Objective: The purpose of this article is to determine whether hepatic artery (HA) Doppler parameters can be used to predict pediatric liver graft status in the immediate postoperative (< 10 days) period and in the first year after transplant., Materials and Methods: A retrospective review of the liver transplant database was performed to review operative, clinical, laboratory, histopathologic, and ultrasound findings at three time points after surgery: 3 days, 3 months, and 1 year. The association between HA velocity and resistive index (RI) with graft status was assessed., Results: Of 120 children (54 girls and 66 boys; mean age, 3 years 2 months) enrolled, 70 had satisfactory graft status at the 1-year follow-up examination. HA velocity of 50-200 cm/s at 3 days was associated with normal graft status during the immediate postoperative period (p = 0.003), at 3 months (p = 0.0653), and at the 1-year follow-up examination (p = 0.0268). Vascular and biliary complications in the immediate postoperative period were more frequent at an HA velocity of 201-300 cm/s (p = 0.0024). There was a significant association between RI at 3 days and graft status in the immediate postoperative period (p = 0.0308), with an RI less than 0.5 associated with vascular complications (p = 0.0116)., Conclusion: An RI less than 0.5 is associated with vascular complications. An HA velocity of 50-200 cm/s and an RI of 0.5-0.8 are associated with normal graft status in children within the first year after transplant. Values outside this range, or in this range along with a constellation of other ultrasound findings and clinical status, support the initiation of additional more-specific investigations that may help in early treatment to prevent complications.

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., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: To examine whether SMOFlipid prevents progression of intestinal failure-associated liver disease (IFALD) in parenteral nutrition (PN)-dependent infants with early IFALD (conjugated bilirubin 17-50 µmol/L, 1-3 mg/dL)., Study Design: Pilot multicenter blinded randomized controlled trial comparing SMOFlipid with Intralipid. Patients received the trial lipid for up to 12 weeks, unless they achieved full enteral tolerance sooner. The primary clinical outcome was the serum conjugated bilirubin., Results: Twenty-four infants (mean age, 6 weeks) participated in the trial (13 Intralipid and 11 SMOFlipid). At the time of trial enrollment, patients in both groups were receiving 90% of their calories by PN. Mean duration on trial was 8 weeks and did not differ according to treatment ( P = .99). At trial conclusion, patients who received SMOFlipid had a lower conjugated bilirubin than those who received Intralipid (mean difference, -59 µmol/L; P = .03). Patients receiving SMOFlipid were also more likely to have a decrease in serum conjugated bilirubin to 0 µmol/L than those in the Intralipid group over the entire observation period (hazard ratio, 10.6; 95%; P = .03). The time to achievement of full enteral tolerance did not differ statistically (hazard ratio, 1.3; P = .59) between the groups. There was no significant difference in safety outcomes between the groups., Conclusions: Compared with Intralipid, SMOFlipid reduces the risk of progressive IFALD in children with intestinal failure. This trial was registered at clinicaltrials.gov as NCT00793195.

Background: Pediatric intestinal failure (PIF) is a life-altering chronic condition with significant morbidity and mortality. Omegaven® therapy has been used to treat children with advanced intestinal failure associated liver disease. Our objective was to determine the evolution of hepatic fibrosis in PIF patients who received Omegaven® and describe their clinical outcome., Methods: A retrospective review in PIF patients who received Omegaven® was performed. Patients were included if they had liver biopsies completed before Omegaven® therapy and after resolution of hyperbilirubinemia. Biopsy results were evaluated to determine the degree of fibrosis, inflammation, and cholestasis. Clinical and biochemical data was collected., Results: Six patients were identified. Assessment of fibrosis at last follow-up demonstrated improvement in 2 patients and progression or stable fibrosis in 4/6. All patients demonstrated reduction in cholestasis and inflammation. One patient received a liver/intestine transplant and a second is listed, both of them with progressive fibrosis. One patient achieved full enteral nutrition, while the rest remain partially parenteral nutrition dependent., Conclusion: Use of Omegaven® is associated with reduced cholestasis and inflammation, but with persistence or worsening of fibrosis in some patients. A subset of patients with progressive fibrosis may develop portal hypertension and progressive liver disease., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Children with short bowel syndrome (SBS) often require numerous operations to optimize intestinal function. Postoperative intestinal strictures are a complication that inhibits enteral feeding advancement and prolongs parenteral nutrition dependency, often requiring reoperation. Our objective was to review our experience with fluoroscopic balloon dilatation to treat intestinal strictures., Methods: A retrospective cohort study of intestinal failure patients with SBS was completed. Patients who had radiologically diagnosed intestinal strictures and treated with fluoroscopic guided balloon dilatation were included [n=6]. Data related to demographics, anatomy, surgical procedures, and dilatation procedures were collected. Descriptive summary statistics were employed., Results: 98 intestinal failure patients were recruited between 2011 and 2015. Five of 98 patients (5.1%) [2 males; median age 4.4months] underwent fluoroscopy guided balloon dilatation of 6 strictures. Balloon dilatation was successful in 4/6 (67%). The median number of dilatations was 2 per patient (range=1-3). Median time to feed initiation postdilatation was 3days. One patient developed an anastomotic leak after dilatation that required antibiotics, but no reoperation., Conclusion: Four of six (67%) postoperative bowel strictures in 5 patients with SBS were successfully treated with fluoroscopically guided balloon dilatation. Balloon dilatation is less invasive than reoperation, preserves bowel length and reduces time to reinitiation of enteral feeding., Level of Evidence: 3., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Vitamin D deficiency is common in patients with intestinal failure and short bowel syndrome who have been weaned of parenteral nutrition. Dietary supplementation with vitamin D is necessary to correct this deficiency. In certain cases, routine supplementation strategy may be ineffective. We report 3 cases of vitamin D deficiency in patients with intestinal failure who showed improvement in serum 25-hydroxyvitamin D levels after supplementation with a loading dose of 20,000-40,000 IU vitamin D provided weekly.

Background. Assessment of school readiness evaluates physical, social-emotional, and neuropsychological domains essential for educational success. Cognitive testing of preschool aged children with chronic liver disease may guide more timely interventions and focused efforts by health care providers. Patients and Methods. Children with chronic cholestatic liver disease diagnosed as an infant and still with their native liver (NL) and children who received a liver transplant (LT) before age of 2 years underwent testing with a battery of well-validated pediatric psychometric measures. Results. Eighteen (13 LT, 5 NL) patients (median age of 4.45 and 4.05 years, resp.) were tested. Median Full-Scale IQ was 98 (range 102-116) for LT and 116 [(range 90-106), p = 0.35, NS] for NL subjects. LT recipients had significantly greater visual based difficulties, poorer caregiver rated daily living skills ( p = 0.04), and higher levels of executive function based difficulties (e.g., inattention, inhibition). Conclusion. This pilot study highlights the risk of neuropsychological difficulties in early school age children who were under 2 years of age at time of LT. Comprehensive early school age assessment should integrate psychometric measures to identify children at greatest risk, thus allowing for proactive educational intervention., Competing Interests: The authors declare that there is no conflict of interests regarding the publication of this paper.

Background: The survival rate of infants and children with intestinal failure is increasing, necessitating a greater focus on their developmental trajectory., Aims: To evaluate neurodevelopmental outcomes in children with intestinal failure at 0-15months corrected age., Study Design: Analysis of clinical, demographic and developmental assessment results of 33 children followed in an intestinal rehabilitation program between 2011 and 2014. Outcome measures included: Prechtl's Assessment of General Movements, Movement Assessment of Infants, Alberta Infant Motor Scale and Mullen Scales of Early Learning. Clinical factors were correlated with poorer developmental outcomes at 12-15months corrected age., Results: Thirty-three infants (17 males), median gestational age 34weeks (interquartile range 29.5-36.0) with birth weight 1.98kg (interquartile range 1.17-2.50). Twenty-nine (88%) infants had abnormal General Movements. More than half had suspect or abnormal scores on the Alberta Infant Motor Scale and medium to high-risk scores for future neuromotor delay on the Movement Assessment of Infants. Delays were seen across all Mullen subscales, most notably in gross motor skills. Factors significantly associated with poorer outcomes at 12-15months included: prematurity, low birth weight, central nervous system co-morbidity, longer neonatal intensive care admission, necrotizing enterocolitis diagnosis, number of operations and conjugated hyperbilirubinemia., Conclusion: Multiple risk factors contribute to early developmental delay in children with intestinal failure, highlighting the importance of close developmental follow-up., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening systemic disease, characterized by overwhelming stimulation of the immune system and categorized as primary or secondary types. Occasionally, acute liver failure (ALF) may dominate the clinical presentation. Given the systemic nature of HLH and risk of recurrence, HLH is considered by many a contraindication to liver transplantation (LT). The aim of this study is to review our single-center experience with LT in children with secondary HLH and ALF (HLH-ALF). This is a cross-sectional, retrospective study of children with secondary HLH-ALF that underwent LT in 2005-2014. Of 246 LTs, 9 patients (3 males; median age, 5 years; range, 0.7-15.4 years) underwent LT for secondary HLH-ALF. Disease progression was rapid with median 14 days (range, 6-27 days) between first symptoms and LT. Low fibrinogen/high triglycerides, elevated ferritin, hemophagocytosis on liver biopsy, and soluble interleukin 2 receptor levels were the most commonly fulfilled diagnostic criteria; HLH genetic studies were negative in all patients. Immunosuppressive therapy after LT included corticosteroids adjusted to HLH treatment protocol and tacrolimus. Thymoglobulin (n = 5), etoposide (n = 4), and alemtuzumab (n = 2) were used in cases of recurrence. Five (56%) patients experienced HLH recurrence, 1 requiring repeat LT, and 3 died. Overall graft and patient survival were 60% and 67%, respectively. Six patients are alive and well at a median of 24 months (range, 15-72 months) after transplantation. In conclusion, LT can be beneficial in selected patients with secondary HLH-ALF and can restore good health in an otherwise lethal condition. Liver Transplantation 22 1245-1253 2016 AASLD., (© 2016 by the American Association for the Study of Liver Diseases.)

Objectives: Surveillance of hepatic nodules for malignant transformation to hepatocellular carcinoma is important in the monitoring of patients with biliary atresia (BA). To date, only 2 published case reports describe the finding of hepatoblastoma (HB) in this setting. The present study aimed to investigate this association of HB and BA, and to assess the utility of alpha-fetoprotein (aFP) as a marker in the diagnosis., Methods: A retrospective study of all patients who underwent isolated liver transplantation (LTx) for the primary diagnosis of BA at a single center, between January 1999 and June 2014, was conducted. Patient demographics, pre-LTx aFP levels, and histologic examination of native liver explants were reviewed., Results: One hundred two (44% men, median age 11 months) patients underwent LTx for BA. Two (2%) explants examinations were confirmatory for concomitant HB; both patients had abnormally elevated aFP. Overall, 56 (55%) patients had available pre-LTx aFP levels. Recipients with persistently abnormal aFP levels (n = 20, 36%) were older at hepatoportoenterostomy (107 vs 68 days, P = 0.02) and younger at LTx surgery (359 vs 1713 days, P < 0.01), compared to patients with constantly normal levels (n = 24, 43%)., Conclusions: In our cohort, HB was found to coexist in approximately 2% of patients with BA undergoing LTx, far exceeding the hypothetical anticipated incidence of 1:10 billion for the concomitant diagnoses. Elevated serum aFP levels may be sensitive but not specific for HB in this context. Further research is required to identify specific mechanisms and risk factors.

Background: The clinical picture of pediatric intestinal failure has changed over the past 15 years, while effectiveness evolving treatment options remains unclear. This study explored evolution in care and quantified independent effects of new treatment options., Study Design: Consecutive patients (n = 196) with neonatal or infantile intestinal failure, born between July 1996 and December 2011, were derived from an intestinal rehabilitation program (IRP) patient registry. Change over time was analyzed using multivariable Box-Jenkins method-based autoregressive integrative moving average models (ARIMA), robust linear regression, and nonparametric trend analysis. Four systematically introduced treatment options (IRP, serial transverse enteroplasty, omega-3 lipid emulsions, and ethanol locks) were evaluated. Analyses were adjusted for patient characteristics and disease severity. The primary outcome was disease-specific mortality from liver failure and sepsis. Secondary outcomes included parenteral nutrition weaning, transplantations, catheter complications, and liver disease., Results: Patient characteristics remained unchanged over time, except for decreasing small bowel length (-0.5%/quarter; 95% CI -0.85, -0.16) and ICU admission time (-0.6 days/quarter; 95% CI -1.03, -0.18). Disease-specific mortality diminished significantly over time (-0.02 deaths/quarter; 95% CI -0.03, -0.01) by IRP and omega-3 lipids introduction (-0.6 deaths/quarter each, 95% CI -1.23, -0.02 and -0.77, -0.45, respectively). Serial transverse enteroplasty and ethanol locks had no significant impact. Parenteral nutrition weaning and transplantations remained unchanged, while catheter sepsis and complication rates decreased by 0.3 episodes/1,000 catheter-days each (95% CI -0.43, -0.2 and -0.45, -0.24, respectively)., Conclusions: Introduction of IRP and omega-3 lipids independently decreased disease-specific mortality. For the first time, time series analysis was applied to evaluate effectiveness of treatment options in intestinal rehabilitation., (Copyright © 2016 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

A subset of human regulatory T cells (Tregs) can secrete IFN-γ or IL-17, and thus share features of TH1 or TH17 effector cells and lose suppressive function. The main factors driving this differentiation of Tregs toward a proinflammatory phenotype include IL-12 for TH1-like and IL-6 for TH17-type Tregs. In this study we show that Tregs of patients with de novo autoimmune hepatitis (dAIH) display increased frequencies of proinflammatory IFN-γ and IL-17 cytokines. Irrespective of a fully demethylated FOXP3 locus, Tregs of subjects with dAIH are functionally impaired. In line with the observed Treg phenotype, we detected the presence of two dominant cytokines (IL-12 and IL-6) clustering with CD68(+) monocyte/macrophage cells in livers of subjects with dAIH, and isolated monocytes of subjects with dAIH secrete high levels of proinflammatory IL-12 and IL-6, suggesting that this inflammatory milieu is key for functional impairment of Tregs. Importantly, the blockade of IFN-γ partially restores suppressive function of Tregs of subjects with dAIH, indicating that monocyte/macrophage-derived triggers might play a central role in Treg dysfunction and pathogenesis of dAIH., (Copyright © 2016 by The American Association of Immunologists, Inc.)

Background: Outcomes of children with intestinal failure have improved over the last decade. However, with improved survival, other co-morbidities have become evident. The goal of our study was to evaluate the presence of renal nephrocalcinosis or increased echogenicity in a cohort of patients with pediatric intestinal failure (PIF)., Methods: A cross-sectional prevalence design was performed in PIF patients followed by our intestinal rehabilitation program between 2013 and 2014. Renal function was evaluated using serum creatinine and urea, urine oxalate, creatinine, calcium, and calcium/creatinine ratios. Renal ultrasounds were performed to assess for echogenicity. Data was collected on intestinal failure related factors and nutritional intake. Data was analyzed using medians and Mann-Whitney U or proportions and chi square., Results: Fifty-four patients (median age 48months; 33 males (61%) were studied. Twenty-two patients (41%) had increased echogenicity or nephrocalcinosis on ultrasound. There were no differences in serum Creatinine or urea, but patients with nephrocalcinosis had statistically different calcium:creatinine ratio (1.69 vs 0.74; p=0.043), urine oxalate (108 vs 219; p=0.06), and serum phosphate (1.55 vs 1.75; p=0.044). Patients with echogenicity had a shorter colonic remnant (25cm vs 31cm; p=0.01), a history of longer PN exposure (928 vs 483days; p=0.05), percent PN calories (37 vs 0; p=0.05), PN h/day (13 vs 0; p=0.05), but no difference in PN Ca/phosphate/magnesium content (mmol/kg)., Conclusion: A large proportion of PIF patients have increased echogenicity/nephrocalcinosis on ultrasound that is associated with prolonged PN exposure. This has implications for long-term management. Regular surveillance is required, and further study is warranted to determine specific risk factors., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Survival of children with intestinal failure has improved over the last decade, resulting in increased health care expenditures. Our objective was to determine outpatient costs for the first year after primary discharge., Methods: A retrospective analysis was performed in pediatric intestinal failure (PIF) patients between 2010 and 2012. Patients were stratified into 3 groups (1=enteral support with no devices [7 patients], 2=enteral support with devices (gastrostomy and/or ostomy) [19 patients], 3=home parenteral nutrition (HPN) [22 patients]). Data abstraction included clinical characteristics and costs related to medication, enteral/parenteral nutrition, and supplies were calculated. Data were analyzed using one way ANOVA., Results: Forty-eight patients (mean age 7.6months; 31 males [65%]) were studied. See attached table for results. HPN patients had significantly more ambulatory visits (p<0.0001), number of admitted days (p=0.01), and productive days lost (p<0.0001). Total cost of care was significantly higher for HPN patients (mean=$320,368.50, p<0.0001) when compared to other groups. Costs covered by the health care system were significantly higher for patients on HPN (mean=$316,101.56, p<0.0001)., Conclusion: The outpatient expenditures to care for PIF patients in the first year post primary discharge are significant. Our single payer health care system supports the majority of costs, but families are also incurring expenses related to travel and lost productivity. Children on HPN have more visits to hospital, but have access to more funding options. Children solely on gastrostomy or stoma therapy, however, have a significantly greater personal financial burden., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Enteral autonomy and freedom from parenteral nutrition dependency is the ultimate therapeutic goal in children with intestinal failure. This can be achieved following attainment of bowel adaptation in conditions such as short bowel syndrome. Enteral nutrition is a major therapeutic cornerstone in the management of children with intestinal failure. It promotes physiological development, bowel adaptation and enhances weaning from parenteral nutrition. The optimal method of delivery, type of nutrients, timing of initiation, promotion of feeds and transition to solid food in children with short bowel syndrome are debated. Lack of high quality human data hampers evidence based conclusions and impacts daily practices in the field. Clinical approaches and therapeutic decisions are regularly influenced by expert opinion and center practices. This review summarizes the physiological principles, medical evidence and practice recommendations on enteral nutrition approaches in short bowel syndrome and provides a practical framework for daily treatment of this unique group of patients. Oral and tube feeding, bolus and continuous feeding, type of nutrients, formulas, trace elements and solid food options are reviewed. Future collaborative multicenter, high quality clinical trials are needed to support enteral nutrition approaches in intestinal failure., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Extracorporeal photopheresis (ECP) culls pathogenic T lymphocytes, be these the clones of cutaneous T-cell lymphoma, or mediators of chronic graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT-GVHD). Whether or not ECP may have an effect in the rarer instances of solid organ transplantation-associated GVHD (SOT-GVHD) is unclear. Mortality rates in SOT-GVHD rival those of transfusion-associated GVHD, with fatalities preceded by pancytopenia and peripheral blood chimerism (PBC) levels exceeding 20%. ECP has been described in two SOT-GVHD cases to date, with one surviving., Study Design and Methods: Clinicolaboratory features (including HLA relationships) in a case of multivisceral transplantation were reviewed from the time of surgery to the onset and progression of SOT-GVHD. ECP, which was introduced as a less immunosuppressive and more selective intervention, was assessed for its effect on serial PBC (as measured by short-tandem-repeat analysis) and clinical outcome., Results: Multivisceral SOT-GVHD manifested with erythroderma, neutropenic sepsis, and PBC increasing from 6% on Posttransplant Day (PTD) 38 to 78% by PTD 60 (at a doubling time of 6 days despite corticosteroids). ECP was administered on PTDs 62 and 67 and was associated with the first evidence of PBC decay to 67% on PTD 69. Death nevertheless ensued on the last day of salvage antithymocyte globulin (PTDs 69-73) despite further PBC reduction to 41%., Conclusion: Further study is needed to determine if the sooner or more frequent application of ECP might attenuate the high case fatality rates of SOT-GVHD., (© 2016 AABB.)

This study analyzed how features of a liver graft and the technique of biliary reconstruction interact to affect biliary complications in pediatric liver transplantation. A retrospective analysis was performed of data collected from 2001 to 2011 in a single high-volume North American pediatric transplant center. The study cohort comprised 173 pediatric recipients, 75 living donor (LD) and 98 deceased donor (DD) recipients. The median follow-up was 70 months. Twenty-nine (16.7%) patients suffered a biliary complication. The majority of leaks (9/12, 75.0%) and the majority of strictures (18/22, 81.8%) were anastomotic. There was no difference in the rate of biliary complications associated with DD (18.4%) and LD (14.7%) grafts (P = 0.55). Roux-en-Y (RY) reconstruction was associated with a significantly lower rate of biliary complications compared to duct-to-duct reconstruction (13.3% versus 28.2%, respectively; P = 0.048). RY anastomosis was the only significant factor protecting from biliary complications in our population (hazard ratio, 0.30; 95% confidence interval, 0.1-0.85). The leaks were managed primarily by relaparotomy (10/12, 83.3%), and the majority of strictures were managed by percutaneous biliary intervention (14/22, 63.6%). Patients suffering biliary complications had inferior graft survival (P = 0.04) at 1, 5, and 10 years compared to patients without biliary complications. Our analysis demonstrates a lower incidence of biliary complications with RY biliary reconstruction, and patients with biliary complications have decreased graft survival., (© 2015 American Association for the Study of Liver Diseases.)

Objectives: The outcome of children with intestinal failure has improved during the past decade following the introduction of novel therapies by dedicated intestinal rehabilitation programs (IRP). The aim of the present study was to assess the impact of IRP on the outcome of intestinal transplant (IT) candidates and the transplant waiting list., Methods: A retrospective cohort study of children assessed for IT (n = 84) during a 10-year period. Comparisons were made among the following 3 time periods: before the establishment of our center's IRP (1999-2002; n = 33), early IRP (2003-2005; n = 18), and late IRP (2006-2009; n = 33). The following endpoints were used: patient outcome following IT assessment (not listed, listed and removed from the list, received transplant, died while on the list), patient characteristics at IT assessment, and patient status at the end of the study., Results: The late-IRP era was associated with an increase in patients who were not listed (42% vs 28% at other periods, P = NS) and patients who were removed from the IT waiting list because of clinical improvement (P < 0.0005), and a decrease in those who died before transplant (15% vs >60% at other periods, P < 0.0005). The cause of death shifted from traditional causes such as liver failure or sepsis to other comorbid conditions (P < 0.005). Improved liver function at listing was also observed during late IRP (P < 0.005)., Conclusions: Treatment by IRP, coupled with recent advances in the medical management of intestinal failure, is associated with improved survival and outcome of patients waiting for IT, and may lead to overall reduction in the number of IT in the future.

Background & Aims Methods: Severe intestinal diseases observed in very young children are often the result of monogenic defects. We used whole exome sequencing (WES) to examine the genetic cause in a patient with a distinct severe form of protein losing enteropathy (PLE) characterized by hypoproteinemia, hypoalbuminemia, and hypertriglyceridemia., Methods: WES was performed at the Centre for Applied Genomics, Hospital for Sick Children, Toronto, Canada. Exome library preparation was performed using the Ion Torrent AmpliSeq RDY Exome Kit. Functional studies were carried out based on the identified mutation., Results: Using whole exome sequencing we identified a homozygous nonsense mutation (1072C>T; p.Arg358*) in the PLVAP (plasmalemma vesicle associated protein) gene in an infant from consanguineous parents who died at five months of age of severe protein losing enteropathy. Functional studies determined that the mutated PLVAP mRNA and protein were not expressed in the patient biopsy tissues, presumably secondary to nonsense-mediated mRNA decay. Pathological analysis showed that the loss of PLVAP resulted in disruption of endothelial fenestrated diaphragms., Conclusions: PLVAP p.Arg358* mutation resulted in loss of PLVAP expression with subsequent deletion of the diaphragms of endothelial fenestrae leading to plasma protein extravasation, protein-losing enteropathy and ultimately death., Competing Interests: The authors have no potential conflicts including financial, professional, or personal that are relevant to the manuscript.

Background: Patients receiving long-term parenteral nutrition (PN) are at increased risk of aluminium (Al) toxicity because of bypass of the gastrointestinal tract during PN infusion. Complications of Al toxicity include metabolic bone disease (MBD), Al-associated encephalopathy in adults, and impaired neurological development in preterm infants. Unlike the United States, there are no regulations regarding Al content of large- and small-volume parenterals in Canada. We, therefore, aimed to present our data on plasma Al concentration and Al intake from our cohort of pediatric patients receiving long-term PN., Methods: Plasma Al concentration was retrospectively gathered from the patient charts of all 27 patients with intestinal failure (IF) receiving long-term PN at The Hospital for Sick Children, Toronto, Canada, and compared with age- and sex-matched controls recruited for comparison. In addition, Al concentration was measured in PN samples collected from 10 randomly selected patients with IF and used to determine their Al intake., Results: The plasma Al concentration of patients with IF receiving long-term PN was significantly higher than that of control participants (1195 ± 710 vs 142 ± 63 nmol/L; P < .0001). In the subgroup of 10 patients for whom Al intake from their PN solution was determined, mean ± SD Al intake from PN was 15.4 ± 15 µg/kg, 3 times the Food and Drug Administration upper recommended intake level, and Al intake was significantly related to plasma Al concentration (P = .02, r (2) = 0.52)., Conclusion: Pediatric patients receiving long-term PN for IF in Canada are at risk for Al toxicity., (© 2014 American Society for Parenteral and Enteral Nutrition.)

Background: Transition to adult-centered care is becoming an increasingly important area of practice in pediatric organ transplant. Standardized, best-practice guidelines are needed to assist transplant practitioners in providing optimal transitional care for this population of patients., Objective: To describe the development and implementation of a practice guideline for the transitional care of pediatric transplant recipients., Methods: A quality improvement project was undertaken in a pediatric multiorgan transplant program setting. Strategies employed included (1) creation of an interdisciplinary working group, (2) survey of transition-related practices and learning needs of transplant practitioners, (3) review of the literature and existing transition-related materials, and (4) creation of transition guidelines., Results: An interdisciplinary survey of transplant practitioners at our institution identified practice strengths related to transitional care and learning needs. Review of relevant literature and other materials revealed limited but emerging research related to the transition of pediatric transplant recipients from pediatric to adult care. Existing transition tools were examined and applicable items identified. A practice guideline for use with pediatric transplant recipients transitioning to adult care was developed. Strategies to educate staff about the guideline and promote ongoing guideline use were implemented., Conclusion: Preparing pediatric transplant recipients and their families for transition to adult-centered care is an emerging challenge for transplant teams. These guidelines provide practitioners with a developmentally sensitive overview of important transition-related domains and strategies directed toward patients and their caregivers, who may experience the process of transition differently. Dissemination of the pediatric transplant transition guideline will make transition information more widely available to transplant practitioners.

Background: Long-term survival after paediatric liver transplantation is now the rule rather than the exception. Improving long-term outcomes after transplantation must consider not only the quantity but also the quality of life years restored., Objectives: To characterize health-related quality of life (HRQOL) of LT recipients ≥15 years after paediatric LT., Methods: Recipients of a paediatric LT performed before December 1996 in a single institution with continuous follow-up at either the paediatric or adult partner centre were identified. Patients with severe developmental or neurological impairment were excluded. HRQOL was assessed using the Pediatric Quality of Life Inventory 4.0, the Medical Outcomes Study Short Form-36 version 2 and the Pediatric Liver Transplant Quality of Life Tool., Results: A total of 27 (67% male) subjects (mean age 24.3±6.7 years [median 23.2 years; range 16.6 to 40.3 years]) participated. The median age at transplant was 1.7 years (range 0.5 to 17.0 years). Seven (26%) participants underwent retransplantation. Seventeen (63%) participants were engaged in full-time work/study. Mean Short Form-36 version 2 scores included physical (49.6±11.1) and mental (45.3±12.5) subscale scores. The mean score for the disease-specific quality of life tool for paediatric liver transplant recipients (the Pediatric Liver Transplant Quality of Life Tool) was 64.70±15.2. The physical health of the young adults strongly correlated with level of involvement in work/study (r=0.803; P<0.05)., Conclusions: The self-reported HRQOL of participants <18 years of age was comparable with a standardized healthy population. In contrast, participants between 18 and 25 years of age had HRQOL scores that were more similar to a group with chronic illness. Participants engaged in full-time work/study experienced enhanced physical health.

Unlabelled: PTMS describes the presence of ≥3 cardiometabolic risk factors that include obesity, hypertension, dyslipidemia, and IR. The prevalence of the clustering of ≥3 cardiometabolic risk factors or central obesity has not been studied in pediatric LT recipients. Single-center, cross-sectional study., Inclusion Criteria: LT recipients 2-18 yr-old, at least one yr post-LT., Exclusion Criteria: recipients of liver retransplants or multivisceral transplants. Eighty-seven patients were identified. Median age was 9.8 yr (range 2-18), median time since LT was 6.9 yr (range 1-17). The most common indication for LT was biliary atresia (56%), and the most frequently used immunosuppressant was tacrolimus (80%). The prevalence of overweight and obesity was 21% and 5%, respectively. Central obesity affected 14%, hypertension 44%, IR 27%, low HDL 20%, and hypertriglyceridemia 39% of patients. The prevalence of ≥3 cardiometabolic risk factors was 19%. Fifty percent of the overweight/obese patients had ≥3 risk factors. Time since transplant, immunosuppression and renal function were not different between those with <3 or ≥3 risk factors. Clustering of cardiometabolic risk factors is prevalent in pediatric LT recipients, suggesting an increased risk of future CV events., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background/aim: Wire-guided cannulation (WGC) of the common bile duct may be associated with fewer complications and higher success rate compared with contrast-guided cannulation (CGC) in adults. Data in children are lacking. The aim of this study was to compare the successful cannulation and complication rate of WGC and CGC in pediatric endoscopic retrograde cholangiopancreatography (ERCP)., Patients and Methods: We report a retrospective cohort study comparing WGC to CGC in a pediatric cohort. We reviewed the medical records of 167 children who underwent ERCP over a 10-year time period (CGC, 1999-2003, WGC, 2003-2009). Indications, findings, and success were analyzed., Results: A total of 93 patients (56%) underwent WGC and 74 (44%) CGC. Children in the WGC group were younger (9.5 ± 4.7 vs. 11.5 ± 4.6 years in CGC; P = 0.006) and underwent more therapeutic ERCP interventions (70% vs. 40% in CGC), whereas diagnostic ERCP was more common in the CGC group (60%; P < 0.005). The overall success (96%) and complication rate (8%) were identical in both groups but a trend toward a reduction in the complication rate over time was noted in the WGC group. Post-ERCP pancreatitis (PEP) was documented in one patient in the WGC group (1.1%) and three patients (4.2%) in the CGC group (P-NS)., Conclusion: The success and complication rate in both CGC and WGC are comparable in children but considering the patient and procedure complexity and the trend toward lower PEP in the WGC group, WGC may be the preferable cannulation technique for ERCP in children.

Background: Metabolic bone disease (MBD) is a well-recognized but poorly understood complication of long-term parenteral nutrition (PN). Bone histomorphometry in adults has provided useful information but does not provide quantitative measures of bone resorption and is to invasive for children. Measurement of bone turnover markers provides an alternative less invasive approach. We therefore aimed to measure bone turnover markers in children on long-term PN for intestinal failure (IF), and to compare them to age- and gender-matched controls., Methods: Serum concentrations of osteocalcin (OC), bone-specific alkaline phosphatase (BSAP), and c-telopeptide (CTx) were measured in IF patients treated at a multidisciplinary intestinal rehabilitation and home PN program at the Hospital for Sick Children, Toronto, Canada. Age- and gender-matched control participants were recruited for comparison., Results: A total of 13 IF patients and 20 control participants were recruited. IF patients had lower serum OC and CTx concentrations when compared with controls: 42.43 ± 11.54 vs 68.39 ± 20.95 µg/L (P < .01) and 7.454 ± 2.17 vs 9.246 ± 1.92 (P < .05; mean ± SD) µg/L for OC and CTx, respectively. In a subgroup of 9 IF patients for whom BMD was available, OC and CTx concentration were negatively correlated to BMD (g/cm(2)) and BMD z score., Conclusion: Bone turnover markers may be useful indicators for identifying children on long-term PN at risk of MBD. Further studies are needed to validate the current results and determine the factors that influence the occurrence and evolution of MBD in children on PN., (© 2013 American Society for Parenteral and Enteral Nutrition.)

Background & Aims: Very early onset inflammatory bowel diseases (VEOIBD), including infant disorders, are a diverse group of diseases found in children younger than 6 years of age. They have been associated with several gene variants. Our aim was to identify the genes that cause VEOIBD., Methods: We performed whole exome sequencing of DNA from 1 infant with severe enterocolitis and her parents. Candidate gene mutations were validated in 40 pediatric patients and functional studies were carried out using intestinal samples and human intestinal cell lines., Results: We identified compound heterozygote mutations in the Tetratricopeptide repeat domain 7 (TTC7A) gene in an infant from non-consanguineous parents with severe exfoliative apoptotic enterocolitis; we also detected TTC7A mutations in 2 unrelated families, each with 2 affected siblings. TTC7A interacts with EFR3 homolog B to regulate phosphatidylinositol 4-kinase at the plasma membrane. Functional studies demonstrated that TTC7A is expressed in human enterocytes. The mutations we identified in TTC7A result in either mislocalization or reduced expression of TTC7A. Phosphatidylinositol 4-kinase was found to co-immunoprecipitate with TTC7A; the identified TTC7A mutations reduced this binding. Knockdown of TTC7A in human intestinal-like cell lines reduced their adhesion, increased apoptosis, and decreased production of phosphatidylinositol 4-phosphate., Conclusions: In a genetic analysis, we identified loss of function mutations in TTC7A in 5 infants with VEOIBD. Functional studies demonstrated that the mutations cause defects in enterocytes and T cells that lead to severe apoptotic enterocolitis. Defects in the phosphatidylinositol 4-kinase-TTC7A-EFR3 homolog B pathway are involved in the pathogenesis of VEOIBD., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Recently, genetic associations have been described in intestinal transplants. Namely, Crohn's disease susceptibility gene NOD2 polymorphisms have been reported to be more prevalent in patients with graft failure following intestinal transplantation (IT). Therefore, we sought to determine if polymorphisms in the NOD2 signaling cascade, including NOD2, CARD9, RAC1 and ATG16L1 are associated with intestinal failure (IF) or its complications. We carried out a cross-sectional study of 59 children with IF and 500 healthy Caucasian controls. Using the Taqman platform we determined the prevalence of NOD2 as well as ATG16L1, RAC1 and CARD9 SNPs. NOD2 pathway polymorphisms were evaluated in relation to outcomes of episodes of sepsis, ICU admissions, hyperbilirubinemia and need for IT. We found that the minor allele of a CARD9 SNP was associated with protection from developing IF when compared to healthy controls and was also associated with decreased odds of sustained conjugated hyperbilirubinemia. Therefore, IF patients with CARD9 polymorphism are less likely to develop progressive liver disease and suggests that host innate immunity may play a role in IF associated liver disease.

Microvillus inclusion disease (MVID) is a congenital enteropathy characterized by loss of apical microvilli and formation of cytoplasmic inclusions lined by microvilli in enterocytes. MVID is caused by mutations in the MYO5B gene, coding for the myosin Vb motor protein. Although myosin Vb is implicated in the organization of intracellular transport and cell surface polarity in epithelial cells, its precise role in the pathogenesis of MVID is unknown. We performed correlative immunohistochemistry analyses of sections from duodenal biopsies of a MVID patient, compound heterozygous for two novel MYO5B mutations, predicting loss of function of myosin Vb in duodenal enterocytes together with a stable MYO5B CaCo2 RNAi cell system. Our findings show that myosin Vb-deficient enterocytes display disruption of cell polarity as reflected by mislocalized apical and basolateral transporter proteins, altered distribution of certain endosomal/lysosomal constituents including Rab GTPases. Together, this severe disturbance of epithelial cell function could shed light on the pathology and symptoms of MVID., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: Tufting enteropathy (TE) is a classical congenital disorder of the intestinal mucosa causing protracted diarrhea in infancy as a result of a dysfunctional epithelial cell barrier, which is mainly caused by mutations in the EpCAM gene and expression of a nonfunctional epithelial cell adhesion molecule in the intestine. We report here a novel nonsense mutation in a patient suspected of having TE, resulting in a complete absence of EpCAM in duodenal enterocytes., Methods: A patient presenting with congenital diarrhea and suspected of having TE was screened for EpCAM mutations, and duodenal biopsies were stained for EpCAM using immunohistochemistry analysis., Results: We identified a novel homozygous nonsense mutation in the EpCAM gene in a patient suspected of having TE, causing a complete loss of EpCAM expression in duodenal enterocytes., Conclusions: With screening analysis for EpCAM mutations and immunohistochemistry for EpCAM expression in duodenal enterocytes, we found a novel homozygous mutation in a patient with classical protracted diarrhea in infancy finally diagnosed as TE, which results in a complete absence of EpCAM and in dysfunctional barrier formation in duodenal enterocytes.

Goals: The aim of this report is to delineate the clinical, pathologic, and enteroendocrine (EE) features of prohormone convertase 1/3 (PC1/3) deficiency in children., Background: Prohormone convertases play a pivotal role in the activation of biologically inactive hormones. Congenital defects in the EE axis, such as PC1/3 deficiency, have been rarely reported and their pathophysiological mechanisms are largely unknown., Study: EE function and pathology was evaluated in 4 males (1, 2, 7, and 10 y old) from 2 families with PC1/3 deficiency at a university children's hospital. Clinical course, pathology analysis including immunohistochemistry for PC1/3, PC2, and glucagon-like peptide 1 (GLP-1) and electron microscopy, as well as EE function tests (GLP-1, GLP-2, oral glucose tolerance test) were performed., Results: All (n=4) suffered from congenital severe diarrhea associated with malabsorption. The diarrhea improved during the first year of life and hyperphagia with excessive weight gain (BMI>97th percentile) became the predominant phenotype at an older age. Analysis of the enteroendocrine axis revealed high proinsulin levels (57 to 1116 pmol/L) in all patients, low serum GLP-2 levels, and impaired insulin and GLP-1 secretion after an oral glucose tolerance test at a young age, with improvement in 1 older child tested. Electron microscopy showed normal ultrastructure of enterocytes and EE cells. Immunohistochemistry revealed normal expression of chromogranin A, a marker of EE cells but markedly reduced immunostaining for PC1/3 and PC2 in all patients., Conclusions: PC1/3 deficiency is associated with an age dependent, variable clinical phenotype caused by severe abnormalities in intestinal and EE functions. Serum level of proinsulin can be used as an effective screening tool.

Background & Aims: Proprotein convertase 1/3 (PC1/3) deficiency, an autosomal-recessive disorder caused by rare mutations in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene, has been associated with obesity, severe malabsorptive diarrhea, and certain endocrine abnormalities. Common variants in PCSK1 also have been associated with obesity in heterozygotes in several population-based studies. PC1/3 is an endoprotease that processes many prohormones expressed in endocrine and neuronal cells. We investigated clinical and molecular features of PC1/3 deficiency., Methods: We studied the clinical features of 13 children with PC1/3 deficiency and performed sequence analysis of PCSK1. We measured enzymatic activity of recombinant PC1/3 proteins., Results: We identified a pattern of endocrinopathies that develop in an age-dependent manner. Eight of the mutations had severe biochemical consequences in vitro. Neonates had severe malabsorptive diarrhea and failure to thrive, required prolonged parenteral nutrition support, and had high mortality. Additional endocrine abnormalities developed as the disease progressed, including diabetes insipidus, growth hormone deficiency, primary hypogonadism, adrenal insufficiency, and hypothyroidism. We identified growth hormone deficiency, central diabetes insipidus, and male hypogonadism as new features of PCSK1 insufficiency. Interestingly, despite early growth abnormalities, moderate obesity, associated with severe polyphagia, generally appears., Conclusions: In a study of 13 children with PC1/3 deficiency caused by disruption of PCSK1, failure of enteroendocrine cells to produce functional hormones resulted in generalized malabsorption. These findings indicate that PC1/3 is involved in the processing of one or more enteric hormones that are required for nutrient absorption., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Congenital ultra-short bowel syndrome (USBS) is a challenging problem with a poor outcome. We report a new management approach for USBS infants that attempts to optimize gut growth potential., Methods: We report five neonates with USBS in whom no correction was performed at primary surgery except placement of a gastrostomy (G) tube. Sham feeds were started with intermittent G-tube clamping to induce bowel dilatation/growth. Serial fluoroscopy was done until bowel caliber reached 5 cm. STEP was performed and continuity established to the colonic remnant. Small bowel length (SBL) and enteral caloric intake were tabulated., Results: Patients were born with a mean residual SBL of 19 ± 7.6 cm (14.8% of expected). Median duration of sham feeds prior to STEP was 108 (range 27-232)days. Mean SBL at STEP was 47 ± 12.1cm, which increased post-STEP to 70 ± 12.7 cm (a mean increase of 296% from birth, representing 36.4% ± 13.1% of expected gut length). With a median follow-up time of 20 months (range 8-28), 4/5 achieved >50% enteral calories and have normal liver function. One has undergone liver transplantation., Conclusions: In USBS patients, delayed surgical correction with sham feeds accelerates gut growth, optimizing potential for autologous reconstruction. This approach may offer greater opportunity for intestinal adaptation than traditional options., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Pediatric intestinal failure (IF) is a complex clinical problem requiring coordinated multi-disciplinary care. Our objective was to review the evidence for the benefit of intestinal rehabilitation programs (IRP) in pediatric IF patients., Methods: A systematic review was performed on Medline (1950-2012), Pubmed (1966-2012), and Embase (1980-2012) conference proceedings and trial registries. The terms short bowel syndrome, intestinal rehabilitation, intestinal failure, patient care teams, and multi-disciplinary teams were used. Fifteen independent studies were included. Three studies that were cohort studies, including a comparison group, were included in a meta-analysis., Results: Compared to historical controls (n=103), implementation of an IRP (n=130) resulted in a reduction in septic episodes (0.3 vs. 0.5 event/month; p=0.01) and an increase in overall patient survival (22% to 42%). Non-significant improvements were seen in weaning from PN (RR=1.05, 0.88-1.25, p=0.62), incidence of IFALD (RR=0.2, 0-17.25, p=0.48), and relative risk of liver transplantation (3.99, 0.75-21.3, p=0.11). Other outcomes reported included a reduction in calories from parenteral nutrition (100% to 32%-56%), earlier surgical/transplant evaluation, and improved coordination of patient care., Conclusion: For pediatric IF patients, IRPs are associated with reduced morbidity and mortality. Standardized clinical practice guidelines are necessary to provide uniform patient care and outcome assessment., (Copyright © 2013 Elsevier Inc. All rights reserved.)