Publications by authors named "Simon C Ling"

94 Publications

Highly multiplexed 2-dimensional imaging mass cytometry analysis of HBV-infected liver.

JCI Insight 2021 Feb 23. Epub 2021 Feb 23.

Department of Medical Research, The Corporal Michael J. Crescenz VA Medical Center, Philadelphia, United States of America.

Studies of human hepatitis B virus (HBV) immune pathogenesis are hampered by limited access to liver tissues and technologies for detailed analyses. Here, utilizing imaging mass cytometry (IMC) to simultaneously detect 30 immune, viral and structural markers in liver biopsies from patients with HBeAg+ chronic hepatitis B, we provide novel comprehensive visualization, quantitation and phenotypic characterizations of hepatic adaptive and innate immune subsets that correlated with hepatocellular injury, histological fibrosis and age. We further show marked correlations between adaptive and innate immune cell frequencies and phenotype, highlighting complex immune interactions within the hepatic microenvironment with relevance to HBV pathogenesis.
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http://dx.doi.org/10.1172/jci.insight.146883DOI Listing
February 2021

Magnetic Resonance Liver Lymphangiography for Investigation and Transhepatic Lymphatic Embolization for the Treatment of Protein-Losing Enteropathy.

J Vasc Interv Radiol 2021 02 29;32(2):327-329.e2. Epub 2020 Nov 29.

Division of Image Guided Therapy, Department of Diagnostic Imaging, The Hospital for Sick Children, Toronto, ON, Canada; Medical Imaging Department, University of Toronto, ON, Canada.

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http://dx.doi.org/10.1016/j.jvir.2020.10.012DOI Listing
February 2021

Treatment of Chronic Hepatitis C in Young Children Reduces Adverse Outcomes and Is Cost-Effective Compared with Deferring Treatment to Adulthood.

J Pediatr 2021 Mar 2;230:38-45.e2. Epub 2020 Sep 2.

Toronto Health Economics and Technology Assessment (THETA) Collaborative, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

Objective: To evaluate the cost-effectiveness of treating young children with chronic hepatitis C virus (HCV) with new direct-acting antivirals.

Study Design: A state-transition model of chronic HCV was developed to conduct a cost-effectiveness analysis comparing treatment at age 6 years vs delaying treatment until age 18 years. Model inputs were derived from recently conducted systematic reviews, published literature, and government statistics. Medical care costs were obtained from linked population level laboratory and administrative data (Ontario, Canada). Outcomes are expressed in expected quality-adjusted life-years and costs (CAD$). Analysis included a base-case to estimate the expected value and one-way and probabilistic sensitivity analyses to evaluate the impact of uncertainty of the model inputs.

Results: After 20 years, treating 10 000 children early would prevent 330 cases of cirrhosis, 18 cases of hepatocellular carcinoma, and 48 liver-related deaths. The incremental cost-effectiveness ratio of early treatment compared to delayed treatment was approximately $12 690/quality-adjusted life-years gained and considered cost-effective. Model results were robust to variation in fibrosis progression rates, disease state-based costs, treatment costs, and utilities.

Conclusions: Delaying treatment until age 18 years results in an increased lifetime risk of late-stage liver complications. Early treatment in children is cost effective. Our work supports clinical and health policies that broaden HCV treatment access to young children.
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http://dx.doi.org/10.1016/j.jpeds.2020.08.088DOI Listing
March 2021

Pediatric Wilson Disease Presenting as Acute Liver Failure: An Individual Patient Data Meta-analysis.

J Pediatr Gastroenterol Nutr 2020 09;71(3):e90-e96

Division of Gastroenterology, Hepatology, and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Canada.

Objectives: Wilson disease (WD) presenting as acute liver failure (ALF) is rare and typically fatal without liver transplantation (LT). Its rarity has hindered comprehensive studies. We undertook an individual patient data meta-analysis to characterize a cohort of pediatric patients presenting with ALF whose final diagnosis was WD to examine outcomes and identify predictors of poor outcomes.

Methods: Database searches were conducted in PubMed, ScienceDirect, and Google Scholar, restricted to English-language articles published between January 1984 and May 2018. Articles were excluded if pediatric (<18 years old) data were not extractable or if LT was not readily available at reporting institutions. Extracted data included clinical and biochemical characteristics, genotype, treatment, and outcome.

Results: Data were available on 249 subjects from 52 articles, plus 7 additional subjects identified from our institution's WD database (N = 256). Females represented 69% (n = 170/245). Median age at presentation was 13.4 years (n = 204, range 4.0-17.9). Of the total 256 subjects, 87% underwent LT, 11% achieved spontaneous recovery and 2% died before LT. International normalized ratio >2.0 at presentation was a predictor of LT/death (odds ratio 7.6, 95% confidence interval 1.5-28), with a trend observed for hepatic encephalopathy (HE) (odds ratio 4.18, 95% confidence interval 0.99-18). Arithmetic diagnostic scores proved inferior in the pediatric age-bracket compared to adults.

Conclusions: This large international pediatric cohort has permitted an individual patient data analysis of WD presenting as ALF. Notably, 11% of subjects achieved spontaneous survival; the rest required LT. Coagulopathy (international normalized ratio >2:0) and HE at presentation heralded poor outcomes. Further prospective studies may identify additional early predictors of outcomes.
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http://dx.doi.org/10.1097/MPG.0000000000002777DOI Listing
September 2020

Hepatic Histology in Treatment-naïve Children With Chronic Hepatitis B Infection Living in the United States and Canada.

J Pediatr Gastroenterol Nutr 2020 07;71(1):99-105

Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.

Objectives: Chronic hepatitis B virus infection is a major cause of morbidity and mortality. The aim of the study is to describe the hepatic histology in children chronically infected with hepatitis B virus living in the United States and Canada.

Methods: Liver biopsies of 134 treatment-naïve children with chronic hepatitis B virus infection were scored for inflammation, fibrosis, and other histological features, and correlated with clinical and laboratory data.

Results: Sixty percentage of subjects acquired the infection vertically, 51% were male, and 69% were hepatitis B e antigen-positive at the time of the biopsy. Hepatitis B DNA levels were generally high (mean 7.70 log IU/mL), as was serum alanine aminotransferase (median 120 U/L). Using the Ishak-modified histology activity index scoring system, interface hepatitis was mild in 31%, moderate in 61%, and severe in 6%. Lobular inflammation was mild in 54%, moderate in 29%, and marked in 7%. Portal inflammation was mild in 38% and moderate in 62% of subjects. Eighteen percentage had no fibrosis, 59% had portal expansion without bridging fibrosis, 19% had bridging fibrosis, and 4% had cirrhosis. Alanine aminotransferase positively correlated with inflammation and fibrosis. Neither age, duration of infection, nor Hepatitis B virus DNA levels correlated with fibrosis. Fibrosis-4 index did not correlate with fibrosis but correlated with inflammation. Aspartate aminotransferase/platelet ratio index correlated with both inflammation and fibrosis.

Conclusions: Chronic hepatitis B virus infection results in significant inflammation and fibrosis during childhood. Serum alanine aminotransferase is a strong indicator of the severity and extent of hepatic inflammation and fibrosis.
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http://dx.doi.org/10.1097/MPG.0000000000002712DOI Listing
July 2020

TIPS for Kids: Are We at the Tipping Point?

Authors:
Simon C Ling

J Pediatr Gastroenterol Nutr 2020 05;70(5):539-540

Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Canada.

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http://dx.doi.org/10.1097/MPG.0000000000002678DOI Listing
May 2020

Heterogeneous Liver on Research Ultrasound Identifies Children with Cystic Fibrosis at High Risk of Advanced Liver Disease: Interim Results of a Prospective Observational Case-Controlled Study.

J Pediatr 2020 04 12;219:62-69.e4. Epub 2020 Feb 12.

Digestive Health Institute, Children's Hospital Colorado and Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO. Electronic address:

Objective: To assess if a heterogeneous pattern on research liver ultrasound examination can identify children at risk for advanced cystic fibrosis (CF) liver disease.

Study Design: Planned 4-year interim analysis of a 9-year multicenter, case-controlled cohort study (Prospective Study of Ultrasound to Predict Hepatic Cirrhosis in CF). Children with pancreatic insufficient CF aged 3-12 years without known cirrhosis, Burkholderia species infection, or short bowel syndrome underwent a screening research ultrasound examination. Participants with a heterogeneous liver ultrasound pattern were matched (by age, Pseudomonas infection status, and center) 1:2 with participants with a normal pattern. Clinical status and laboratory data were obtained annually and research ultrasound examinations biannually. The primary end point was the development of a nodular research ultrasound pattern, a surrogate for advanced CF liver disease.

Results: There were 722 participants who underwent screening research ultrasound examination, of which 65 were heterogeneous liver ultrasound pattern and 592 normal liver ultrasound pattern. The final cohort included 55 participants with a heterogeneous liver ultrasound pattern and 116 participants with a normal liver ultrasound pattern. All participants with at least 1 follow-up research ultrasound were included. There were no differences in age or sex between groups at entry. Alanine aminotransferase (42 ± 22 U/L vs 32 ± 19 U/L; P = .0033), gamma glutamyl transpeptidase (36 ± 34 U/L vs 15 ± 8 U/L; P < .001), and aspartate aminotransferase to platelet ratio index (0.7 ± 0.5 vs 0.4 ± 0.2; P < .0001) were higher in participants with a heterogeneous liver ultrasound pattern compared with participants with a normal liver ultrasound pattern. Participants with a heterogeneous liver ultrasound pattern had a 9.1-fold increased incidence (95% CI, 2.7-30.8; P = .0004) of nodular pattern vs a normal liver ultrasound pattern (23% in heterogeneous liver ultrasound pattern vs 2.6% in normal liver ultrasound pattern).

Conclusions: Research liver ultrasound examinations can identify children with CF at increased risk for developing advanced CF liver disease.
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http://dx.doi.org/10.1016/j.jpeds.2019.12.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096278PMC
April 2020

Treatment of infants with hepatitis B virus: A window of opportunity?

J Hepatol 2019 11 7;71(5):856-858. Epub 2019 Sep 7.

Division of Pediatric Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

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http://dx.doi.org/10.1016/j.jhep.2019.08.007DOI Listing
November 2019

Phenotypes of Chronic Hepatitis B in Children From a Large North American Cohort.

J Pediatr Gastroenterol Nutr 2019 11;69(5):588-594

Saint Louis University, Saint Louis, MO.

Objective: The aim of the study was to define chronic HBV phenotypes in a large, cohort of United States and Canadian children utilizing recently published population-based upper limit of normal alanine aminotransferase levels (ULN ALT), compared with local laboratory ULN; identify relationships with host and viral factors.

Background: Chronic hepatitis B virus (HBV) infection has been characterized by phases or phenotypes, possibly associated with prognosis and indications for therapy.

Methods: Baseline enrollment data of children in the Hepatitis B Research Network were examined. Phenotype definitions were inactive carrier: HBeAg-negative with low HBV DNA and normal ALT levels; immune-tolerant: HBeAg-positive with high HBV DNA but normal ALT levels; or chronic hepatitis B: HBeAg-positive or -negative with high HBV DNA and abnormal ALT levels.

Results: Three hundred seventy-one participants were analyzed of whom 274 were HBeAg-positive (74%). Younger participants were more likely be HBeAg-positive with higher HBV DNA levels. If local laboratory ULN ALT levels were used, 35% were assigned the immune tolerant phenotype, but if updated ULN were applied, only 12% could be so defined, and the remaining 82% would be considered to have chronic hepatitis B. Among HBeAg-negative participants, only 21 (22%) were defined as inactive carriers and 14 (14%) as HBeAg-negative chronic hepatitis B; the majority (61%) had abnormal ALT and low levels of HBV DNA, thus having an indeterminant phenotype. Increasing age was associated with smaller proportions of HBeAg-positive infection.

Conclusions: Among children with chronic HBV infection living in North America, the immune tolerant phenotype is uncommon and HBeAg positivity decreases with age.
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http://dx.doi.org/10.1097/MPG.0000000000002467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814562PMC
November 2019

Liver Ultrasound Patterns in Children With Cystic Fibrosis Correlate With Noninvasive Tests of Liver Disease.

J Pediatr Gastroenterol Nutr 2019 09;69(3):351-357

Digestive Health Institute, Children's Hospital Colorado & University of Colorado School of Medicine, Aurora, CO.

Objectives: Early identification of children with cystic fibrosis (CF) at risk for severe liver disease (CFLD) would enable targeted study of preventative therapies. There is no gold standard test for CFLD. Ultrasonography (US) is used to identify CFLD, but with concerns for its diagnostic accuracy. We aim to determine if differences in standard blood tests, imaging variables and noninvasive liver fibrosis indices correlate with liver US patterns, and thus provide supportive evidence that a heterogeneous US liver pattern reflects clinically relevant liver disease.

Methods: We studied baseline research abdominal US and bloodwork from 244 children with pancreatic insufficient CF, ages 3 to 12 years, enrolled in a prospective study of the ability of US to predict CF cirrhosis (PUSH study). Children with a heterogeneous (HTG) liver pattern on US (n = 62) were matched 1 : 2 in design with children with normal US (NL, n = 122). Analyses included children with nodular (NOD, n = 22) and homogeneous hyperechoic (HMG, n = 38) livers.

Results: Univariate analysis showed significant differences between US groups for standard blood tests, spleen size, and noninvasive liver fibrosis indices. Multivariable models discriminated NOD versus NL with excellent accuracy (AUROC 0.96). Models also distinguish HTG versus NL (AUROC 0.76), NOD versus HTG (0.78), and HMG versus NL (0.79).

Conclusions: Liver US patterns in children with CF correlate with platelet count, spleen size and indices of liver fibrosis. Multivariable models of these biomarkers have excellent discriminating ability for NL versus NOD, and good ability to distinguish other US patterns, suggesting that US patterns correlate with clinically relevant liver disease.
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http://dx.doi.org/10.1097/MPG.0000000000002413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713487PMC
September 2019

Magnetic Resonance Imaging Assessment of Blood Flow Distribution in Fenestrated and Completed Fontan Circulation with Special Emphasis on Abdominal Blood Flow.

Korean J Radiol 2019 07;20(7):1186-1194

Department of Diagnostic Imaging, The Hospital for Sick Children, University of Toronto, Toronto, Canada.

Objective: To investigate the regional flow distribution in patients with Fontan circulation by using magnetic resonance imaging (MRI).

Materials And Methods: We identified 39 children (18 females and 21 males; mean age, 9.3 years; age range, 3.3-17.0 years) with Fontan circulation in whom flow volumes across the thoracic and abdominal arteries and veins were measured by using MRI. The patients were divided into three groups: fenestrated Fontan circulation group with MRI performed under general anesthesia (GA) (Group 1, 15 patients; average age, 5.9 years), completed Fontan circulation group with MRI performed under GA (Group 2, 6 patients; average age, 8.7 years), and completed Fontan circulation group with MRI performed without GA (Group 3, 18 patients; average age, 12.5 years). The patient data were compared with the reference ranges in healthy controls.

Results: In comparison with the controls, Group 1 showed normal cardiac output (3.92 ± 0.40 vs. 3.72 ± 0.69 L/min/m², = 0.30), while Group 3 showed decreased cardiac output (3.24 ± 0.71 vs. 3.96 ± 0.64 L/min/m², = 0.003). Groups 1 and 3 showed reduced abdominal flow (1.21 ± 0.28 vs. 2.37 ± 0.45 L/min/m², < 0.001 and 1.89 ± 0.39 vs. 2.64 ± 0.38 L/min/m², < 0.001, respectively), which was mainly due to the diversion of the cardiac output to the aortopulmonary collaterals in Group 1 and the reduced cardiac output in Group 3. Superior mesenteric and portal venous flows were more severely reduced in Group 3 than in Group 1 (ratios between the flow volumes of the patients and healthy controls was 0.26 and 0.37 in Group 3 and 0.63 and 0.53 in Group 1, respectively). Hepatic arterial flow was decreased in Group 1 (0.11 ± 0.22 vs. 0.34 ± 0.38 L/min/m², = 0.04) and markedly increased in Group 3 (0.38 ± 0.22 vs. -0.08 ± 0.29 L/min/m², < 0.0001). Group 2 showed a mixture of the patterns seen in Groups 1 and 3.

Conclusion: Fontan circulation is associated with reduced abdominal flow, which can be attributed to reduced cardiac output and portal venous return in completed Fontan circulation, and diversion of the cardiac output to the aortopulmonary collaterals in fenestrated Fontan circulation.
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http://dx.doi.org/10.3348/kjr.2018.0921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609425PMC
July 2019

Pharmacokinetics, Safety, and Efficacy of Glecaprevir/Pibrentasvir in Adolescents With Chronic Hepatitis C Virus: Part 1 of the DORA Study.

Hepatology 2020 02 13;71(2):456-462. Epub 2019 Aug 13.

Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.

The pangenotypic regimen of glecaprevir and pibrentasvir (G/P) is approved to treat adults with chronic hepatitis C virus (HCV) infection and has yielded high cure rates in adults in clinical trials. Approved treatment options for pediatrics may include ribavirin. A pangenotypic regimen for pediatric patients remains an unmet need. DORA is an ongoing phase 2/3, nonrandomized, open-label study evaluating the pharmacokinetics (PK), safety, and efficacy of G/P in pediatric patients with chronic HCV. This analysis includes Part 1 of the study, conducted in adolescent patients 12-17 years of age given the adult regimen of G/P (300 mg/120 mg) once daily for 8-16 weeks according to the indication durations used in adults. Patients were either treatment naïve or experienced with interferon-based regimens. The primary PK endpoint was steady-state exposures for glecaprevir and pibrentasvir; the primary efficacy endpoint was sustained virologic response 12 weeks after treatment (SVR12). The secondary efficacy endpoints were on-treatment virologic failure, relapse, and reinfection. Safety and tolerability were monitored. Part 1 enrolled 48 adolescent patients infected with genotypes 1, 2, 3, or 4, of whom 47 were administered G/P. All 47 patients (100%) achieved SVR12. No on-treatment virologic failures or relapses occurred. PK exposures of glecaprevir and pibrentasvir were comparable to exposures in adults. No adverse events (AEs) led to treatment discontinuation, and no serious AEs occurred. Conclusion: Adolescent patients with chronic HCV infection treated with G/P achieved a comparable exposure to adults, 100% SVR12 rate, and safety profile consistent with that in adults. This pangenotypic regimen demonstrated 100% efficacy within the adolescent population in as little as 8 weeks of treatment.
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http://dx.doi.org/10.1002/hep.30840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028097PMC
February 2020

Portal Angiogenesis in Chronic Liver Disease Patients Correlates with Portal Pressure and Collateral Formation.

Dig Dis 2019 8;37(6):498-508. Epub 2019 May 8.

Department of Pediatric Gastroenterology and Nutrition, Division of Pediatrics, Pontificia Universidad Católica de Chile, Santiago, Chile,

Background/aims: One hallmark of chronic liver disease in patients with portal hypertension is the formation of portal-systemic collaterals in which angiogenesis has a fundamental role. We studied patients with chronic liver disease undergoing liver transplantation to correlate levels of circulating angiogenic factors in portal and peripheral circulation with portal pressure and portal-systemic collaterals.

Methods: Sixteen patients who underwent liver transplantation were enrolled. During transplant surgery, we determined portal venous pressure and portal-systemic collateral formation. We determined angiogenics mediator levels in systemic and portal plasma. Peripheral plasma from healthy donors was measured as controls.

Results: Vascular endothelial growth factor (VEGF)-R1 and 2, Ang-1 and 2, Tie2, FGF- 1 and 2, CD163, PDGFR-β, PDGFsRα, PDGF-AB and BB, CD163, TGF-β VASH-1 levels were significantly different in the controls in comparison to cases. Significantly decreased portal venous levels of Ang-1, FGF-1, PDGF-AB/BB, and CC were observed in patients with higher portal pressure. Peripheral VEGF, Ang-1, pPDGF-AB, BB, and CC were significantly decreased in patients with more severe collateral formation. While peripheral VEGF-R1 was higher in patients with severe collateral formation. For portal circulation, VEGF, Ang-1, -pPDGF-AB, BB, and CC were significantly decreased in patients with more severe collateral formation Conclusions: Angiogenesis factors correlated with portal pressure and collateral formation and different patterns of circulating angiogenesis mediators were found in peripheral and portal blood of patients with chronic liver disease. These results support the importance of angiogenic pathways in cirrhosis and portal hypertension and highlight areas for further study to identify clinically useful noninvasive markers of portal pressure and collateral formation.
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http://dx.doi.org/10.1159/000500115DOI Listing
December 2019

Age, race and viral genotype are associated with the prevalence of hepatitis B e antigen in children and adults with chronic hepatitis B.

J Viral Hepat 2019 07 2;26(7):856-865. Epub 2019 May 2.

University of California at San Francisco, San Francisco, California.

Hepatitis B e antigen (HBeAg) is an important serological marker of hepatitis B virus (HBV) infection and is associated with higher levels of viraemia, increased risk of infectivity to others and increased risk of hepatocellular carcinoma. We analysed HBeAg status in a large cohort of adults and children enrolled in Cohort Studies of the Hepatitis B Research Network, long-term natural history studies of chronic HBV infection. A cross-sectional analysis examined factors associated with HBeAg positivity, including demographic and virologic data, across the age spectrum. Among 2241 enrolled participants who met criteria for this analysis, 825 (37%) were seropositive for HBeAg. The prevalence of HBeAg was lower in those with older age, ranging from 85% among those up to 10 years of age to only 12% among those older than 50 years. In addition to age, both race and HBV genotype were independently associated with HBeAg positivity. There was a significant interaction between age and race; the prevalence of HBeAg was significantly higher among Asians > 10-30 years old vs Whites or Blacks who were >10 to 30 years old and those infected with HBV genotype C. Conversely, the presence of the basal core promoter and precore variants was associated with significantly lower prevalence of HBeAg, even when adjusted for age, race and genotype. These data will provide a better understanding of factors associated with seropositivity for HBeAg and may lead to better strategies for preventing HBV infection and broader indications for antiviral therapy.
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http://dx.doi.org/10.1111/jvh.13104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592737PMC
July 2019

A Multidisciplinary Approach to Pretransplant and Posttransplant Management of Cystic Fibrosis-Associated Liver Disease.

Liver Transpl 2019 04 20;25(4):640-657. Epub 2019 Mar 20.

Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX.

Approximately 5%-10% of patients with cystic fibrosis (CF) will develop advanced liver disease with portal hypertension, representing the third leading cause of death among patients with CF. Cystic fibrosis with advanced liver disease and portal hypertension (CFLD) represents the most significant risk to patient mortality, second only to pulmonary or lung transplant complications in patients with CF. Currently, there is no medical therapy to treat or reverse CFLD. Liver transplantation (LT) in patients with CFLD with portal hypertension confers a significant survival advantage over those who do not receive LT, although the timing in which to optimize this benefit is unclear. Despite the value and efficacy of LT in selected patients with CFLD, established clinical criteria outlining indications and timing for LT as well as disease-specific transplant considerations are notably absent. The goal of this comprehensive and multidisciplinary report is to present recommendations on the unique CF-specific pre- and post-LT management issues clinicians should consider and will face.
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http://dx.doi.org/10.1002/lt.25421DOI Listing
April 2019

Achieving High-quality Outcomes for Endoscopic Retrograde Cholangiopancreatography: Can Pediatricians Match the Adults, and Should They Try?

J Pediatr Gastroenterol Nutr 2019 01;68(1):1-2

Division of Gastroenterology, Hepatology and Nutrition, the Learning and Research Institutes, Hospital for Sick Children, Department of Paediatrics and the Wilson Centre, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1097/MPG.0000000000002103DOI Listing
January 2019

Can Pediatric Endoscopists Accurately Assess Their Clinical Competency? A Comparison Across Skill Levels.

J Pediatr Gastroenterol Nutr 2019 03;68(3):311-317

Division of Gastroenterology, Hepatology and Nutrition.

Background: Assessment is critical to support pediatric endoscopy training. Although trainee engagement in assessment is encouraged, the use of self-assessment and its accuracy among pediatric endoscopists is not well described. We aimed to determine the self-assessment accuracy of novice, intermediate, and experienced pediatric endoscopists.

Methods: Novice (performed <50 previous colonoscopies), intermediate (50-500), and experienced (>1000) pediatric endoscopists from 3 North American academic teaching hospitals each performed a clinical colonoscopy. Endoscopists were assessed in real-time by 2 experienced endoscopists using the Gastrointestinal Endoscopy Competency Assessment Tool for Pediatric Colonoscopy (GiECATKIDS). In addition, participants self-assessed their performance using the same instrument. Self-assessment accuracy between the externally assessed and self-assessed scores was evaluated using absolute difference scores, intraclass correlation coefficients, and Bland-Altman analyses.

Results: Forty-seven endoscopists participated (21 novices, 16 intermediates, and 10 experienced). Overall, there was moderate agreement of externally assessed and self-assessed GiECATKIDS total scores with an intraclass correlation coefficient of 0.72 (95% confidence interval, 0.55-0.83). The absolute difference scores among the 3 groups were significantly different (P = 0.005), with experienced endoscopists demonstrating a more accurate self-assessment compared to novices (P = 0.003). Bland-Altman plots revealed that novice endoscopists' self-assessed scores tended to be higher than their externally assessed scores, indicating they overestimated their performance.

Conclusions: We found that endoscopic experience was positively associated with self-assessment accuracy among pediatric endoscopists. Novices were inaccurate in assessing their endoscopic competence and were prone to overestimation of their performances. Our findings suggest novices may benefit from targeted interventions aimed at improving their insight and self-awareness.
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http://dx.doi.org/10.1097/MPG.0000000000002191DOI Listing
March 2019

Combination of Entecavir/Peginterferon Alfa-2a in Children With Hepatitis B e Antigen-Positive Immune Tolerant Chronic Hepatitis B Virus Infection.

Hepatology 2019 06 20;69(6):2326-2337. Epub 2019 Feb 20.

Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD.

The optimal management strategy for children with immune-tolerant chronic hepatitis B virus (HBV) infection remains unknown. The purpose of this clinical trial was to determine the safety and efficacy of therapy with entecavir and peginterferon in a group of children in the immune-tolerant phase of HBV infection. Children with immune-tolerant features of chronic hepatitis B (CHB) received entecavir once-daily in a dose of 0.015 mg/kg (0.5 mg maximum) for 48 weeks; peginterferon alfa-2a (180 µg/1.73m subcutaneously) once-weekly was added at the end of week 8 and continued until week 48. The primary endpoint was lack of detectable hepatitis B e antigen (HBeAg) with HBV DNA levels ≤1,000 IU/mL 48 weeks after stopping therapy. Sixty children (75% female), median age 10.9 (range, 3.4-17.9) years, were enrolled. All were positive for hepatitis B surface antigen (HBsAg) and HBeAg and had high levels of HBV DNA with normal or minimally elevated levels of alanine aminotransferase (ALT). Fifty-five children completed the entire 48-week course of therapy. At 48 weeks after treatment ended (week 96), 2 children (3%) achieved the primary endpoint and were also HBsAg negative and anti-hepatitis B surface antigen antibody (anti-HBs) positive. One child was HBeAg positive but HBsAg negative at week 60; another was HBeAg negative but HBsAg positive at week 72, which were their last clinic visits. In the remaining children, serum ALT and HBV DNA levels at week 96 were similar to baseline. Thirty-seven children experienced adverse events (AEs), and 1 had a serious AE (SAE). Conclusion: The combination of entecavir and peginterferon for up to 48 weeks rarely led to loss of HBeAg with sustained suppression of HBV DNA levels in children in the immune-tolerant phase of HBV infection, and treatment was associated with frequent AEs.
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http://dx.doi.org/10.1002/hep.30312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465180PMC
June 2019

Analysis of a large cohort of cystic fibrosis patients with severe liver disease indicates lung function decline does not significantly differ from that of the general cystic fibrosis population.

PLoS One 2018 11;13(10):e0205257. Epub 2018 Oct 11.

School of Medicine, Marsico Lung Institute, UNC Cystic Fibrosis Research Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.

Previous reports of lung function in cystic fibrosis (CF) patients with liver disease have shown worse, similar, or even better forced expiratory volume in 1 second (FEV1), compared to CF patients without liver disease. Varying definitions of CF liver disease likely contribute to these inconsistent relationships reported between CF lung function and liver disease. We retrospectively evaluated spirometric data in 179 subjects (62% male; 58% Phe508del homozygous) with severe CF liver disease (CFLD; defined by presence of portal hypertension due to cirrhosis). FEV1 values were referenced to both a normal population (FEV1% predicted) and CF population (CF-specific FEV1 percentile). We utilized a linear mixed model with repeated measures to assess changes in lung function (before and after diagnosis of CFLD), relative to both the normal and CF populations. At diagnosis of CFLD, the mean FEV1 was 81% predicted, or at the 53rd percentile referenced to CF patients without CFLD. There was a significant difference in post-CFLD slope compared to pre-CFLD slope (post-pre) using FEV1% predicted (-1.94, p-value < 0.0001). However, there was insignificant evidence of this difference using the CF-specific FEV1 percentile measure (-0.99, p-value = 0.1268). Although FEV1% predicted values declined in patients following CFLD diagnosis, there was not significant evidence of lung function decline in CF-specific FEV1 percentiles. Thus, the observed study cohort indicates diagnosis of severe CFLD was not associated with worsened CF lung disease when compared to a large CF reference population.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0205257PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6181334PMC
March 2019

Characteristics of Hepatitis B Virus-associated Hepatocellular Carcinoma in Children: A Multi-center Study.

J Pediatr Gastroenterol Nutr 2018 10;67(4):437-440

Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD.

Introduction: Pediatricians and liver specialists in the United States and Canada continue to encounter hepatitis B virus (HBV) infection in high-risk populations, including unvaccinated children, adopted children, and immigrants. Although hepatocellular carcinoma (HCC) is a known complication of HBV, there exists a paucity of data regarding the clinical presentation of HBV-associated HCC in children in these countries.

Methods: Investigators at 4 medical centers with large numbers of HBV-positive children queried their pathology and/or oncology databases to identify all cases of HBV-infected children <18 years old presenting with HCC between 1990 and 2015. Clinical data were extracted from chart review.

Results: The group identified 8 patients, 8 to 17 years old, including 6 (75%) males. All individuals were assumed to be infected through vertical transmission. Three (38%) presented initially to the emergency room, 2 (25%) to a general pediatrician, 1 (13%) to a hepatologist, and the initial location was not documented in 2 (25%) cases. Three patients were asymptomatic, but the most common symptoms were abdominal pain (50%) and fatigue (38%). Hepatomegaly was present in 5 (63%) patients. Viral load was not documented in any patient. Only 3 patients had their HBeAg status documented and all individuals were HBeAg(-) and anti-HBe(+). Aspartate aminotransferase (AST) ranged from 13 to 575 IU/L, and alanine aminotransferase (ALT) ranged from 14 to 212 IU/L; 4 patients had AST and ALT < 1.5 times the upper limit of normal. Three patients had elevated bilirubin and gamma glutamyl transpeptidase (GGT), and 3 had normal bilirubin and GGT; 1 patient had unknown bilirubin and a separate patient had unknown GGT. Alpha-fetoprotein (AFP) was elevated in 3 patients (range 2.556-7.600 ng/mL), normal in 2 patients, and not documented in 3 patients. Ultrasound was initially used to identify the tumor in 5 patients whereas computerized axial tomography scan was used in 3 patients. Six patients had multiple nodules on initial imaging.

Conclusions: Although rare, HBV-associated HCC occurs in young children, often with normal liver enzymes, bilirubin, GGT, and AFP. Only routine imaging with ultrasound or computerized axial tomography scan consistently identified the tumor. These data may help inform screening for HCC including age of initiation and the role for imaging over laboratory testing.
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http://dx.doi.org/10.1097/MPG.0000000000002093DOI Listing
October 2018

Acute Variceal Bleeding Causes Significant Morbidity.

J Pediatr Gastroenterol Nutr 2018 09;67(3):371-376

Division of Gastroenterology, Hepatology and Nutrition, Department of Paediatrics.

Background And Aims: The need for primary prophylaxis of variceal bleeding in children is unclear due to insufficient evidence of the efficacy of prophylactic therapy and the mortality and morbidity associated with the first bleeding event. Previous studies have provided estimates of mortality. We aimed to investigate the morbidity associated with acute variceal bleeding (AVB) in children and to identify contributing factors.

Methods: We retrospectively reviewed children with chronic liver disease or portal vein thrombosis admitted with acute upper gastrointestinal bleeding between 2000 and 2015.

Results: Seventy AVB episodes in 57 children (median age 6 years, 52% girls) were included, 58% with cirrhosis and 30% portal vein thrombosis. Approximately 67% were the patient's first bleed. Post-AVB morbidity was present in 57% of all episodes and in 64% of first bleeds and included: ascites (34%), infection (30%), respiratory complications (24%), intensive care unit admission (20%), rebleed (11%), encephalopathy (7%), acute kidney injury (6%), and failure to control bleed (4%). Two patients died (4% of first bleeds, 8% of cirrhotics' first bleeds) within 6 weeks of bleeding. Median length of stay was 7 days. Overall morbidity was associated with total bilirubin (P = 0.001). Ascites after AVB was associated with pediatric end-stage liver disease (P = 0.0007), total bilirubin (P = 0.001), and cirrhosis (P = 0.006). Median length of stay was longer in patients with morbidities (18 vs 4 days, P < 0.0001).

Conclusion: Children with AVB suffer significant morbidity but have a low risk of death. Morbidity should therefore be considered in future studies measuring the risks and benefits of primary prophylaxis of first AVB in children.
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http://dx.doi.org/10.1097/MPG.0000000000002039DOI Listing
September 2018

New Onset Autoimmune Hepatitis during Anti-Tumor Necrosis Factor-Alpha Treatment in Children.

J Pediatr 2018 03 21;194:128-135.e1. Epub 2017 Dec 21.

Hospital for Sick Children, Toronto, Ontario, Canada. Electronic address:

Objectives: To evaluate a large anti-tumor necrosis factor (TNF)-treated pediatric inflammatory bowel disease cohort for drug-induced liver injury (DILI) following presentation of an index case with suspected DILI with autoimmune features after infliximab exposure. To characterize the incidence, natural history, and risk factors for liver enzyme elevation with anti-TNF use.

Study Design: We reviewed the index case and performed a retrospective cohort study of 659 children receiving anti-TNF therapy between 2000 and 2015 at a tertiary pediatric inflammatory bowel disease center. Patients with alanine aminotransferase (ALT) ≥×2 the upper limit of normal were included. The incidence, evolution, and risk factors for liver injury were examined with univariate and multivariable proportional hazards regression. Causality was assessed using the Roussel-Uclaf Causality Assessment Method.

Results: The index case, a teenage girl with Crohn's disease, developed elevated liver enzymes and features of autoimmune hepatitis on liver biopsy 23 weeks after starting infliximab. The injury resolved entirely within 4 months of withdrawing infliximab without additional therapy. Overall, 7.7% of our cohort developed new ALT elevations while on anti-TNF. Most ALT elevations were mild and transient and attributable to alternate etiologies. No additional clear cases of autoimmune hepatitis were identified.

Conclusions: Transient liver enzyme abnormalities are relatively common among anti-TNF-treated children. Anti-TNF-related DILI with autoimmune features is rare but must be recognized so that therapy can be stopped.
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http://dx.doi.org/10.1016/j.jpeds.2017.10.071DOI Listing
March 2018

Impact of experience on self-assessment accuracy of clinical colonoscopy competence.

Gastrointest Endosc 2018 Mar 6;87(3):827-836.e2. Epub 2017 Nov 6.

Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; The Wilson Centre, University of Toronto, Toronto, Ontario, Canada.

Background And Aims: Self-assessment is important for life-long learning and a recommended assessment method for endoscopy skills. Prior literature has not investigated self-assessment accuracy of colonoscopic competence in the clinical setting. This study aimed to determine the self-assessment accuracy of novice, intermediate, and experienced endoscopists.

Methods: Novice (performed <50 previous colonoscopies), intermediate (50-500), and experienced (>1000) endoscopists from 5 hospitals each performed a clinical colonoscopy. Video recordings of procedures were independently assessed by 2 blinded expert endoscopists by using the Gastrointestinal Endoscopy Competency Assessment Tool (GiECAT). Externally assessed and self-assessed GiECAT scores were defined as the mean of the 2 video-based ratings and as participants' own assigned ratings, respectively. Self-assessment accuracy between the externally assessed and self-assessed scores was evaluated by using absolute difference scores, intraclass correlation coefficients, and the Bland-Altman analysis.

Results: Twenty novice, 10 intermediate, and 10 experienced endoscopists participated. There was moderate agreement of externally assessed and self-assessed GiECAT scores, with an intraclass correlation coefficient of 0.65 (95% confidence interval, 0.44-0.80). The absolute difference scores among the 3 groups were significantly different (P = .002), with experienced endoscopists demonstrating a more accurate self-assessment ability compared with novices (P = .002). Bland-Altman plots suggest that novice and experienced endoscopists tend to overrate and underrate their clinical competence, respectively; no specific trends were associated with intermediates.

Conclusion: Participants demonstrated moderate self-assessment accuracy of clinical competence. Endoscopist experience was positively associated with self-assessment accuracy; novices demonstrated lower self-assessment accuracy compared with experienced endoscopists. Moreover, novices tended to overestimate their performances. Novice endoscopists may benefit from targeted interventions to improve self-assessment accuracy.
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http://dx.doi.org/10.1016/j.gie.2017.10.040DOI Listing
March 2018

A prospective comparison of live and video-based assessments of colonoscopy performance.

Gastrointest Endosc 2018 Mar 30;87(3):766-775. Epub 2017 Aug 30.

Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; Wilson Centre, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

Background And Aims: Colonoscopy performance is typically assessed by a supervisor in the clinical setting. There are limitations of this approach, however, because it allows for rater bias and increases supervisor workload demand during the procedure. Video-based assessment of recorded procedures has been proposed as a complementary means by which to assess colonoscopy performance. This study sought to investigate the reliability, validity, and feasibility of video-based assessments of competence in performing colonoscopy compared with live assessment.

Methods: Novice (<50 previous colonoscopies), intermediate (50-500), and experienced (>1000) endoscopists from 5 hospitals participated. Two views of each colonoscopy were videotaped: an endoscopic (intraluminal) view and a recording of the endoscopist's hand movements. Recorded procedures were independently assessed by 2 blinded experts using the Gastrointestinal Endoscopy Competency Assessment Tool (GiECAT), a validated procedure-specific assessment tool comprising a global rating scale (GRS) and checklist (CL). Live ratings were conducted by a non-blinded expert endoscopist. Outcomes included agreement between live and blinded video-based ratings of clinical colonoscopies, intra-rater reliability, inter-rater reliability and discriminative validity of video-based assessments, and perceived ease of assessment.

Results: Forty endoscopists participated (20 novices, 10 intermediates, and 10 experienced). There was good agreement between the live and video-based ratings (total, intra-class correlation [ICC] = 0.847; GRS, ICC = 0.868; CL, ICC = 0.749). Intra-rater reliability was excellent (total, ICC = 0.99; GRS, ICC = 0.99; CL, ICC = 0.98). Inter-rater reliability between the 2 blinded video-based raters was high (total, ICC = 0.91; GRS, ICC = 0.918; CL, ICC = 0.862). GiECAT total, GRS, and CL scores differed significantly among novice, intermediate, and experienced endoscopists (P < .001). Video-based assessments were perceived as "fairly easy," although live assessments were rated as significantly easier (P < .001).

Conclusions: Video-based assessments of colonoscopy procedures using the GiECAT have strong evidence of reliability and validity. In addition, assessments using videos were feasible, although live assessments were easier.
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http://dx.doi.org/10.1016/j.gie.2017.08.020DOI Listing
March 2018

Cystic Fibrosis-related Liver Disease: Research Challenges and Future Perspectives.

J Pediatr Gastroenterol Nutr 2017 10;65(4):443-448

*Pediatric Hepatology Unit, APHP-Hôpital Necker and UPMC Univ Paris 06, INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France †Digestive Health Institute, Children's Hospital Colorado and Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado School of Medicine Aurora, CO ‡Pediatric Gastroenterology and Hepatology, Department Pediatrics, Beatrix Children's Hospital/University Medical Center Groningen, University of Groningen, Groningen, The Netherlands §CF Center, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan, Milan, Italy ||Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, Institute of Cardiometabolism and Nutrition, Institut Hospitalo-Universitaire & Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Centre de Référence Maladies Rares des Maladies Inflammatoires des Voies Biliaires, Service d'Hépatologie, Paris, France ¶Department of Gastroenterology & Hepatology, Erasmus University Medical Center, Rotterdam #Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands **The Liver Unit, Birmingham Children's Hospital, Birmingham, UK ††Division of Gastroenterology, Hepatology & Nutrition, The Hospital for Sick Children, Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada ‡‡Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, Institute of Cardiometabolism and Nutrition, Institut Hospitalo-Universitaire & Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière §§Paris-Descartes, Sorbonne Paris-Cité University, INSERM U-1223 - Pasteur Institute, and Hepatology Unit, Assistance Publique-Hôpitaux de Paris, Cochin Hospital, Paris, France ||||Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria ¶¶Department of Paediatric Gastroenterology, Hepatology and Nutrition University Hospitals Leuven, Leuven, Belgium ##Department of Paediatric Kidney, Liver and Metabolic Diseases, Division of Paediatric Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany ***Pediatric Gastroenterology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.

Objectives: Hepatobiliary complications are a leading cause of morbidity and mortality in cystic fibrosis (CF) patients. Knowledge of the underlying pathological aspects and optimal clinical management is, however, sorely lacking.

Methods: We provide a summary of the lectures given by international speakers at the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) monothematic conference on cystic fibrosis-related liver disease (CFLD) held in Paris in January 2016, to discuss the status of our current knowledge of liver disease in CF patients, to define the critical areas that need to be addressed, and to resolve actions to elucidate relevant mechanisms of disease to optimise future therapeutic options.

Conclusions: The need for a universal consensus on the definition of CFLD to clarify disease stage and to identify relevant biomarkers to assess disease severity was highlighted. A deeper understanding of the pathophysiology and prognostic factors for the long-term evolution of CFLD is fundamental to move forward and has a strong bearing on identifying potential treatments. Novel experimental models and new treatment options under investigation are discussed and offer hope for the near future of CFLD.
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http://dx.doi.org/10.1097/MPG.0000000000001676DOI Listing
October 2017

Splanchnic, Thoracoabdominal, and Cerebral Blood Flow Volumes in Healthy Children and Young Adults in Fasting and Postprandial States: Determining Reference Ranges by Using Phase-Contrast MR Imaging.

Radiology 2017 10 22;285(1):231-241. Epub 2017 May 22.

From the Department of Diagnostic Imaging (P.M., S.J.Y., N.T., J.W., D.S., M.P., P.C.D., M.S., L.G.W., G.B.C.), Division of Cardiology, Department of Pediatrics (S.J.Y., R.C., J.W., D.S., M.P., M.S., L.G.W.), and Division of Gastroenterology, Hepatology, and Nutrition (S.C.L.), the Hospital For Sick Children, 555 University Ave, Toronto, ON, Canada M5G 1X8; and Departments of Medical Imaging (P.M., S.J.Y., P.C.D., M.S., L.G.W., G.B.C.), and Pediatrics (R.C., S.C.L.), University of Toronto, Toronto, Canada.

Purpose To estimate reference ranges for blood flow volume (BFV) in major splanchnic, thoracoabdominal, and neck vessels by using phase-contrast magnetic resonance (MR) imaging in children and young adults in fasting and postprandial states. Materials and Methods In this institutional research ethics board-approved prospective study, healthy volunteers underwent phase-contrast MR imaging in a fasting state and again after a standardized meal. BFV values were reported as medians and ranges, and postmeal to premeal BFV ratios were calculated. BFVs in volunteers divided into two groups according to age (≤18 years old and >18 years old) were compared by using the Mann-Whitney test adjusted for multiple comparisons. Linear regression for internal validation of BFV and Pearson correlation and Bland-Altman analysis for interobserver agreement were used. Results Reference ranges for BFVs were estimated in 39 volunteers (23 male and 16 female; mean age, 21.2 years ± 8.5; range, 9-40 years) and were indexed according to body surface area, with internal validation (R = 0.84-0.92) and excellent interobserver agreement (R = 0.9928). There was an almost 30% increase in total abdominal BFV (P < .0001) in response to a meal, which was the result of a threefold increase in superior mesenteric artery BFV (P < .0001). BFV after the meal remained unaffected in the celiac artery and cerebral circulation. Significantly higher normalized BFVs in the cerebral circulation were measured in children with both preprandial (P = .039) and postprandial (P = .008) status than those in adults. Conclusion Reference ranges for BFVs and changes in BFVs in response to a meal in major splanchnic, thoracoabdominal, and neck vessels were estimated by using phase-contrast MR imaging in healthy volunteers to allow hemodynamic assessment of children and young adults with various diseases. RSNA, 2017 Online supplemental material is available for this article.
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http://dx.doi.org/10.1148/radiol.2017162114DOI Listing
October 2017

The Highs and Lows of Fetal Programming for Fatty Liver Disease.

J Pediatr 2017 08 5;187:13-15. Epub 2017 May 5.

Division of Gastroenterology, Hepatology and Nutrition Department of Pediatrics Hospital for Sick Children Toronto, Ontario, Canada.

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http://dx.doi.org/10.1016/j.jpeds.2017.03.062DOI Listing
August 2017

Platelet count, spleen length, and platelet count-to-spleen length ratio for the diagnosis of oesophageal varices in people with chronic liver disease or portal vein thrombosis.

Cochrane Database Syst Rev 2017 Apr 26;4:CD008759. Epub 2017 Apr 26.

Dipartimento di Scienze Biomediche e Cliniche "L. Sacco", Università degli Studi di Milano, via GB Grassi 74, Milan, Italy, 20157.

Background: Current guidelines recommend screening of people with oesophageal varices via oesophago-gastro-duodenoscopy at the time of diagnosis of hepatic cirrhosis. This requires that people repeatedly undergo unpleasant invasive procedures with their attendant risks, although half of these people have no identifiable oesophageal varices 10 years after the initial diagnosis of cirrhosis. Platelet count, spleen length, and platelet count-to-spleen length ratio are non-invasive tests proposed as triage tests for the diagnosis of oesophageal varices.

Objectives: Primary objectives To determine the diagnostic accuracy of platelet count, spleen length, and platelet count-to-spleen length ratio for the diagnosis of oesophageal varices of any size in paediatric or adult patients with chronic liver disease or portal vein thrombosis, irrespective of aetiology. To investigate the accuracy of these non-invasive tests as triage or replacement of oesophago-gastro-duodenoscopy. Secondary objectives To compare the diagnostic accuracy of these same tests for the diagnosis of high-risk oesophageal varices in paediatric or adult patients with chronic liver disease or portal vein thrombosis, irrespective of aetiology.We aimed to perform pair-wise comparisons between the three index tests, while considering predefined cut-off values.We investigated sources of heterogeneity.

Search Methods: The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Hepato-Biliary Group Diagnostic Test Accuracy Studies Register, the Cochrane Library, MEDLINE (OvidSP), Embase (OvidSP), and Science Citation Index - Expanded (Web of Science) (14 June 2016). We applied no language or document-type restrictions.

Selection Criteria: Studies evaluating the diagnostic accuracy of platelet count, spleen length, and platelet count-to-spleen length ratio for the diagnosis of oesophageal varices via oesophago-gastro-duodenoscopy as the reference standard in children or adults of any age with chronic liver disease or portal vein thrombosis, who did not have variceal bleeding.

Data Collection And Analysis: Standard Cochrane methods as outlined in the Cochrane Handbook for Diagnostic Test of Accuracy Reviews.

Main Results: We included 71 studies, 67 of which enrolled only adults and four only children. All included studies were cross-sectional and were undertaken at a tertiary care centre. Eight studies reported study results in abstracts or letters. We considered all but one of the included studies to be at high risk of bias. We had major concerns about defining the cut-off value for the three index tests; most included studies derived the best cut-off values a posteriori, thus overestimating accuracy; 16 studies were designed to validate the 909 (n/mm/mm cut-off value for platelet count-to-spleen length ratio. Enrolment of participants was not consecutive in six studies and was unclear in 31 studies. Thirty-four studies assessed enrolment consecutively. Eleven studies excluded some included participants from the analyses, and in only one study, the time interval between index tests and the reference standard was longer than three months. Diagnosis of varices of any size. Platelet count showed sensitivity of 0.71 (95% confidence interval (CI) 0.63 to 0.77) and specificity of 0.80 (95% CI 0.69 to 0.88) (cut-off value of around 150,000/mm from 140,000 to 150,000/mm; 10 studies, 2054 participants). When examining potential sources of heterogeneity, we found that of all predefined factors, only aetiology had a role: studies including participants with chronic hepatitis C reported different results when compared with studies including participants with mixed aetiologies (P = 0.036). Spleen length showed sensitivity of 0.85 (95% CI 0.75 to 0.91) and specificity of 0.54 (95% CI 0.46 to 0.62) (cut-off values of around 110 mm, from 110 to 112.5 mm; 13 studies, 1489 participants). Summary estimates for detection of varices of any size showed sensitivity of 0.93 (95% CI 0.83 to 0.97) and specificity of 0.84 (95% CI 0.75 to 0.91) in 17 studies, and 2637 participants had a cut-off value for platelet count-to-spleen length ratio of 909 (n/mm)/mm. We found no effect of predefined sources of heterogeneity. An overall indirect comparison of the HSROCs of the three index tests showed that platelet count-to-spleen length ratio was the most accurate index test when compared with platelet count (P < 0.001) and spleen length (P < 0.001). Diagnosis of varices at high risk of bleeding. Platelet count showed sensitivity of 0.80 (95% CI 0.73 to 0.85) and specificity of 0.68 (95% CI 0.57 to 0.77) (cut-off value of around 150,000/mm from 140,000 to 160,000/mm; seven studies, 1671 participants). For spleen length, we obtained only a summary ROC curve as we found no common cut-off between studies (six studies, 883 participants). Platelet count-to-spleen length ratio showed sensitivity of 0.85 (95% CI 0.72 to 0.93) and specificity of 0.66 (95% CI 0.52 to 0.77) (cut-off value of around 909 (n/mm)/mm; from 897 to 921 (n/mm)/mm; seven studies, 642 participants). An overall indirect comparison of the HSROCs of the three index tests showed that platelet count-to-spleen length ratio was the most accurate index test when compared with platelet count (P = 0.003) and spleen length (P < 0.001). DIagnosis of varices of any size in children. We found four studies including 277 children with different liver diseases and or portal vein thrombosis. Platelet count showed sensitivity of 0.71 (95% CI 0.60 to 0.80) and specificity of 0.83 (95% CI 0.70 to 0.91) (cut-off value of around 115,000/mm; four studies, 277 participants). Platelet count-to-spleen length z-score ratio showed sensitivity of 0.74 (95% CI 0.65 to 0.81) and specificity of 0.64 (95% CI 0.36 to 0.84) (cut-off value of 25; two studies, 197 participants).

Authors' Conclusions: Platelet count-to-spleen length ratio could be used to stratify the risk of oesophageal varices. This test can be used as a triage test before endoscopy, thus ruling out adults without varices. In the case of a ratio > 909 (n/mm)/mm, the presence of oesophageal varices of any size can be excluded and only 7% of adults with varices of any size would be missed, allowing investigators to spare the number of oesophago-gastro-duodenoscopy examinations. This test is not accurate enough for identification of oesophageal varices at high risk of bleeding that require primary prophylaxis. Future studies should assess the diagnostic accuracy of this test in specific subgroups of patients, as well as its ability to predict variceal bleeding. New non-invasive tests should be examined.
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http://dx.doi.org/10.1002/14651858.CD008759.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478276PMC
April 2017

Management of Pediatric Nonalcoholic Fatty Liver Disease by Academic Hepatologists in Canada: A Nationwide Survey.

J Pediatr Gastroenterol Nutr 2017 10;65(4):380-383

*Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Department of Paediatrics, University of Toronto, Toronto, ON †Division of Gastroenterology, Hepatology and Nutrition, BC Children's Hospital, Department of Paediatrics, University of British Columbia, Vancouver, BC.

Background: The literature on the optimal clinical management of pediatric patients with nonalcoholic fatty liver disease (NAFLD) is limited. The objective of this study was to identify discrepancies in the care provided to patients with NAFLD by hepatologists practicing in academic centers across Canada.

Methods: A nationwide survey was distributed electronically to all pediatric hepatologists practicing in university-affiliated hospitals using the infrastructure of the Canadian Pediatric Hepatology Research Group. The responses were anonymous.

Results: The response rate to the survey was 79%. Everyone reported diagnosing NAFLD based on a combination of elevated transaminases and imaging suggestive of steatosis in the context of an otherwise negative workup for other liver diseases. Only 14% use liver biopsy to confirm the diagnosis. There are significant discrepancies in the frequency of screening for other comorbidities (eg, hypertension, sleep apnea, etc) and in the frequency of laboratory investigations (eg, lipid profile, transaminases, international normalized ratio, etc). Frequency of outpatient clinic follow-up varies significantly. Treatment is consistently based on lifestyle modifications; however, reported patient outcomes in terms of body mass index improvements are poor.

Conclusions: There are significant discrepancies in the care provided to children with NAFLD by hepatologists practicing in academic centers across Canada.
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http://dx.doi.org/10.1097/MPG.0000000000001581DOI Listing
October 2017

A national retrospective study of paediatric end-stage liver disease as a predictor of change to second-line therapy in children with autoimmune hepatitis.

Liver Int 2017 10 15;37(10):1562-1570. Epub 2017 Mar 15.

Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON, Canada.

Background & Aims: Adult studies of autoimmune hepatitis (AIH) have shown that the model of end-stage liver disease is associated with resistance to first-line treatment. Using a multicentre retrospective database, we sought to determine if the paediatric end-stage liver disease (PELD) score would similarly predict treatment resistance in paediatric AIH.

Methods: One hundred and seventy-one children from 13 Canadian centres who fulfilled the International Autoimmune Hepatitis Group (IAIHG) criteria were included and assessed for change to second-line therapy within 24 months of primary treatment onset. Those with PSC overlap at presentation, or missing data on the PELD variables were excluded. PELD was calculated for all remaining patients. Univariate analysis and receiver-operator characteristic (ROC) curves were performed to determine the predictive ability of the PELD score to change to second-line therapy.

Results: A total of 103 children were included with median age of 11 years (range 2-17). Mean PELD was -2.51±8.58. Second-line therapy was used within 24 months of diagnosis in 13 patients. Univariate analysis revealed that change to second-line therapy was associated with higher PELD (P=.028) and internal normalized ratio (INR) (P=.011). ROC curves for PELD and its individual components were performed. The strength of association was strongest with INR (AUC 0.72; CI: 0.58-0.86) although the composite PELD score also showed some predictive ability (AUC 0.67; CI: 0.52-0.81).

Conclusion: In this paediatric AIH cohort, higher PELD at presentation predicted change to second-line therapy within the first 2 years of follow-up. INR appeared to be the main contributor to that association.
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http://dx.doi.org/10.1111/liv.13387DOI Listing
October 2017