Introduction: Pediatricians are encouraged to promote behavior modification to reduce childhood obesity and its co-morbidities, yet the effectiveness of office counseling is unclear. We aimed to evaluate if a low-intensity intervention (action-oriented counseling) in a clinic setting results in weight stabilization, and if the effect is modified by a diagnosis of non-alcoholic fatty liver disease (NAFLD). We hypothesized that patients with NAFLD would be more motivated to adhere to the lifestyle goals set in clinic, due to the diagnosis of an obesity-related condition; and, would therefore achieve greater weight reduction compared to similarly overweight and obese patients without a diagnosis of NAFLD. Methods: A retrospective chart review was conducted on 73 (35 male, 38 female) overweight and obese patients (BMI ≥ 85th percentile) attending a pediatric GI clinic between January 2006 and October 2011. Analysis was conducted to determine if lifestyle goals discussed with the patient at each clinic visit were associated with improved BMI, BMI z-score, and liver enzymes. Treatment outcomes among NAFLD patients and similarly obese patients without NAFLD were compared using t-tests and chi-square tests. Results: Of the children evaluated, 74.0% achieved a reduction or stabilization in BMI z-score after 3 months of follow-up. Among NAFLD patients, liver enzymes improved in 72% of those who were able to stabilize or reduce their BMI and among 43% of those who gained weight. Treatment outcome did not significantly differ based on having a diagnosis of NAFLD, although there was a trend towards greater improvements. Conclusion: Our study suggests that action oriented counseling including goal-setting in a low intensity, clinic based approach is effective in improving patient BMI, in the presence or absence of an obesity-related co-morbidity, such as NAFLD. Further, we demonstrated that lifestyle modification led to improvement of liver enzymes in NAFLD patients and may result in other clinically relevant improvements. Longer studies will be needed to determine if the improvements are sustained.
Background:
Split liver transplantation (SLT), where a single donor liver is divided for transplantation to 2 recipients, has the potential to increase the availability of size-matched livers for pediatric candidates and expand the supply of donor organs available for adult candidates. Although SLT is a well-established technique, the number of SLTs has remained flat during the past 2 decades, partly due to concerns about the posttransplant survival of SLT recipients compared with whole liver transplantation (WLT) recipients. Prior work on SLT versus WLT survival analysis had limitations because, for pediatric recipients, it did not consider the correlations between donor age/weight and the allograft type, and for adult recipients, it may have included records where the donor livers did not meet the split liver criteria (splittable).
Methods:
Using the Organ Procurement and Transplantation Network’s database (2003–2019), this study analyzes and compares (i) key characteristics of donors and recipients, (ii) donor-recipient match dynamics (organ offers and accept/decline decisions), and (iii) recipient posttransplant survival, for SLT and WLT.
Results and Conclusions:
The results in this study show that the posttransplant survival of SLT and WLT recipients is similar (controlling for other confounding factors that may impact posttransplant survival), highlighting the importance of SLT for increasing the liver supply and potential benefits for both pediatric and adult candidates.
Background
Crohn’s disease (CD) is highly heritable. NOD2 has emerged as the main susceptibility gene among individuals of European ancestry; however, NOD2 does not appear to contribute to CD susceptibility among many non-European populations. Today’s African American (AA) population represents an admixture of West African (80%) and European (20%) ancestry. Since genotype-based tools are becoming increasingly available for CD, it is important that we validate the risk variants in different populations, such as admixed AAs.
Methods
We analyzed the NOD2 variants among admixed AAs (n=321, 240 with CD and 111 healthy controls) and non-admixed West Africans (n=40) by genotyping for 4 known disease-causing NOD variants. We extracted the publically available 1000 Genomes data on NOD2 variants from 500 subjects of West African origin. Association with disease was evaluated by logistic regression.
Results
An association with CD was found for the classical SNP 1007fs (2.6% CD, 0% HC, p=0.012); there was no association when the genotypic and allelic frequencies of the risk alleles were compared for SNPs R702W and G908R. No known NOD2 risk alleles were seen in either the West African cohort or in subjects of African ancestry from the 1000 Genomes project.
Conclusions
The NOD2 gene is a risk for CD in AAs, although the allele frequencies and the attributable risk are much lower compared to Caucasians. The risk alleles are not seen in the West African population suggesting the risk for CD contributed by NOD2 among AAs is due exclusively to recent European admixture
The transition from pediatric to adult care is a critical time when children with chronic illness sustain high morbidity and mortality. Transition services need to be focused on the adolescents' needs, which may differ from those perceived by healthcare providers. In this study, a survey of 31 patients with chronic liver disease and/or liver transplant who were "transferred" to adult services within the last 3 years was conducted. Patients were asked about their current health status and their perceptions of the overall transfer process. The mean age at transfer was 19.81 (18-21) years. Almost half the patients (47%) were not seen at the adult facility until 2-6 months after leaving the Children's hospital and 20% were not seen until 6-12 months. About 20% had their first contact with adult services through an emergency room visit. About 19% reported being out of medication during transition. Of the transplanted patients, 19% were being evaluated for a retransplant. The majority (82%) felt that an increased emphasis on promoting independence and "letting go" both by parents and by pediatric care providers was critical in their transition to independence and adult care services. This study provides thought-provoking insights, which are critical in designing the ideal transition program for children with chronic diseases.
Background: Nonalcoholic fatty liver disease (NAFLD) has emerged as the major pediatric chronic liver disease, and it is estimated to affect more than one third of obese children in the U.S. Cardiovascular complications are a leading cause of increased mortality in adults with NAFLD and many adolescents with NAFLD already manifest signs of subclinical atherosclerosis including increased carotid intima-media thickness. Methods: Volume of intrahepatic fat was assessed in 50 Hispanic-American, overweight adolescents, using Magnetic Resonance Spectroscopy. Lipoprotein compositions were measured using Nuclear Magnetic Resonance. Results: Plasma triglycerides (TG) (p∈=∈0.003), TG/HDL ratio (p∈=∈0.006), TG/apoB ratio (p∈=∈0.011), large VLDL concentration (p∈=∈0.019), VLDL particle size (p∈=∈0.012), as well as small dense LDL concentration (p∈=∈0.026) progressively increased across higher levels of hepatic fat severity, while large HDL concentration progressively declined (p∈=∈0.043). This pattern of associations remained even after controlling for gender, BMI, visceral fat, and insulin resistance. Conclusions: Our findings suggest that increased hepatic fat is strongly associated with peripheral dyslipidemia and the amount of fat in the liver may influence cardiovascular risk. Further studies are needed to longitudinally monitor dyslipidemia in children with NAFLD and to examine whether the reduction of hepatic fat would attenuate their long-term CVD risk.
by
Tonya Adamiak;
Dorota Walkiewicz-Jedrzejczak;
Daryl Fish;
Christopher Brown;
Jeanne Tung;
Khalid Khan;
William Faubion;
Roger Park;
Janice Heikenen;
Michael Yaffee;
Maria T. Rivera-Bennett;
Marcy Wiedkamp;
Michael Stephens;
Richard Noel;
Melodee Nugent;
Justin Nebel;
Pippa Simpson;
Michael D. Kappelman;
Subramaniam Kugathasan
Background: Epidemiological studies of pediatric inflammatory bowel diseases (IBD) are needed to generate etiological hypotheses and inform public policy; yet, rigorous population-based studies of the incidence and natural history of Crohn's disease (CD) and ulcerative colitis (UC) in the United States are limited. Methods: We developed a field-tested prospective system for identifying all new cases of IBD among Wisconsin children over an 8-year period (2000-2007). Subsequently, at the end of the study period, we retrospectively reconfirmed each case and characterized the clinical course of this incident cohort. Results: The annual incidence of IBD among Wisconsin children was 9.5 per 100,000 (6.6 per 100,000 for CD and 2.4 per 100,000 for UC). Approximately 19% of incident cases occurred in the first decade of life. Over the 8-year study period, the incidence of both CD and UC remained relatively stable. Additionally, (1) childhood IBD affected all racial groups equally, (2) over a follow-up of 4 years, 17% of patients with CD and 13% of patients with patients with UC required surgery, and (3) 85% and 40% of children with CD were treated with immunosuppressives and biologics, respectively, compared with 62% and 30% of patients with UC. Conclusions: As in other North American populations, these data confirm a high incidence of pediatric-onset IBD. Importantly, in this Midwestern U. S. population, the incidence of CD and UC seems to be relatively stable over the last decade. The proportions of children requiring surgery and undergoing treatment with immunosuppressive and biological medications underscore the burden of these conditions.
Fructose-sweetened liquid consumption is associated with fatty liver and oxidative stress. In rodent models of fructose-mediated fatty liver, protein consumption is decreased. Additionally, decreased sulfur amino acid intake is known to cause oxidative stress. Studies were designed to test whether oxidative stress in fructose-sweetened liquid-induced fatty liver is caused by decreased ad libitum solid food intake with associated inadequate sulfur amino acid intake. C57BL6 mice were grouped as: control (ad libitum water), fructose (ad libitum 30% fructose-sweetened liquid), glucose (ad libitum 30% glucose-sweetened water) and pair-fed (ad libitum water and sulfur amino acid intake same as the fructose group). Hepatic and plasma thiol-disulfide antioxidant status were analyzed after five weeks. Fructose- and glucose-fed mice developed fatty liver. The mitochondrial antioxidant protein, thioredoxin-2, displayed decreased abundance in the liver of fructose and glucose-fed mice compared to controls. Glutathione/glutathione disulfide redox potential (E hGSSG) and abundance of the cytoplasmic antioxidant protein, peroxiredoxin-2, were similar among groups. We conclude that both fructose and glucose-sweetened liquid consumption results in fatty liver and upregulated thioredoxin-2 expression, consistent with mitochondrial oxidative stress; however, inadequate sulfur amino acid intake was not the cause of this oxidative stress.
by
Cortney R. Ballengee;
Subramaniam Kugathasan;
Jarod Prince;
Kajari Mondal;
Ryan W. Stidham;
Chunyan Liu;
Mi-Ok Kim;
Robert Baldassano;
Marla Dubinsky;
James Markowitz;
Neal Leleiko;
Jeffrey Hyams;
Lee Denson
Background & Aims: There are few serum biomarkers to identify patients with Crohn's disease (CD) who are at risk for stricture development. The extracellular matrix components, collagen type III alpha 1 chain (COL3A1) and cartilage oligomeric matrix protein (COMP), could contribute to intestinal fibrosis. We investigated whether children with inflammatory CD (B1) who later develop strictures (B2) have increased plasma levels of COL3A1 or COMP at diagnosis, compared with children who remain B1. We compared results with previously studied biomarkers, including autoantibodies against colony-stimulating factor 2 (CSF2). Methods: We selected 161 subjects (mean age, 12.2 y; 62% male) from the Risk Stratification and Identification of Immunogenic and Microbial Markers of Rapid Disease Progression in Children with Crohn's cohort, completed at 28 sites in the United States and Canada from 2008 through 2012. The children underwent colonoscopy and upper endoscopy at diagnosis and were followed up every 6 months for 36 months; plasma samples were collected at baseline. Based on CD phenotype, children were separated to group 1 (B1 phenotype at diagnosis and follow-up evaluation), group 2 (B2 phenotype at diagnosis), or group 3 (B1 phenotype at diagnosis who developed strictures during follow-up evaluation). Plasma samples were collected from patients and 40 children without inflammatory bowel disease (controls) at baseline and analyzed by enzyme-linked immunosorbent assay to measure COL3A1 and COMP. These results were compared with those from a previous biomarker study. The Kruskal–Wallis test and the pairwise Dunn test with Bonferroni correction were used to compare differences among groups. Results: The median baseline concentration of COL3A1 was significantly higher in plasma from group 3 vs group 1 (P < .01) and controls (P = .01). Median baseline plasma concentrations of COMP did not differ significantly among groups. A model comprising baseline concentrations of COL3A1 and anti-CSF2 identified patients with B2 vs B1 CD with an area under the curve of 0.80 (95% CI, 0.71–0.89); the combined concentration identified patients with strictures with a sensitivity value of 0.70 (95% CI, 0.55–0.83) and a specificity value of 0.83 (95% CI, 0.67–0.93). Conclusions: We found median plasma concentrations of COL3A1, measured by enzyme-linked immunosorbent assay at diagnosis, to be significantly higher in patients with CD who later developed strictures than in patients without strictures. The combination of concentrations of COL3A1 and anti-CSF2 might be used to identify pediatric patients at CD diagnosis who are at risk for future strictures. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT00790543.
by
Jeffrey B. Schwimmer;
Joel E. Lavine;
Laura A. Wilson;
Brent A. Neuschwander-Tetri;
Stavra A. Xanthakos;
Rohit Kohli;
Sarah E. Barlow;
Miriam Vos;
Saul Karpen;
Jean P. Molleston;
Peter F. Whitington;
Philip Rosenthal;
Ajay K. Jain;
Karen F. Murray;
Elizabeth M. Brunt;
David E. Kleiner;
Mark L. Van Natta;
Jeanne M. Clark;
James Tonascia;
Edward Doo
Background & Aims No treatment for nonalcoholic fatty liver disease (NAFLD) has been approved by regulatory agencies. We performed a randomized controlled trial to determine whether 52 weeks of cysteamine bitartrate delayed release (CBDR) reduces the severity of liver disease in children with NAFLD. Methods We performed a double-masked trial of 169 children with NAFLD activity scores of 4 or higher at 10 centers. From June 2012 to January 2014, the patients were assigned randomly to receive CBDR or placebo twice daily (300 mg for patients weighing ≤65 kg, 375 mg for patients weighing > 65 to 80 kg, and 450 mg for patients weighing > 80 kg) for 52 weeks. The primary outcome from the intention-to-treat analysis was improvement in liver histology over 52 weeks, defined as a decrease in the NAFLD activity score of 2 points or more without worsening fibrosis; patients without biopsy specimens from week 52 (17 in the CBDR group and 6 in the placebo group) were considered nonresponders. We calculated the relative risks (RR) of improvement using a stratified Cochran–Mantel–Haenszel analysis. Results There was no significant difference between groups in the primary outcome (28% of children in the CBDR group vs 22% in the placebo group; RR, 1.3; 95% confidence interval [CI], 0.8–2.1; P =.34). However, children receiving CBDR had significant changes in prespecified secondary outcomes: reduced mean levels of alanine aminotransferase (reduction, 53 ± 88 U/L vs 8 ± 77 U/L in the placebo group; P =.02) and aspartate aminotransferase (reduction, 31 ± 52 vs 4 ± 36 U/L in the placebo group; P =.008), and a larger proportion had reduced lobular inflammation (36% in the CBDR group vs 21% in the placebo group; RR, 1.8; 95% CI, 1.1–2.9; P =.03). In a post hoc analysis of children weighing 65 kg or less, those taking CBDR had a 4-fold better chance of histologic improvement (observed in 50% of children in the CBDR group vs 13% in the placebo group; RR, 4.0; 95% CI, 1.3–12.3; P =.005). Conclusions In a randomized trial, we found that 1 year of CBDR did not reduce overall histologic markers of NAFLD compared with placebo in children. Children receiving CBDR, however, had significant reductions in serum aminotransferase levels and lobular inflammation. ClinicalTrials.gov no: NCT01529268.
by
David J Cutler;
Michael Zwick;
David T. Okou;
Sampath Prahalad;
Thomas Walters;
Stephen L. Guthery;
Marla Dubinsky;
Robert Baldassano;
Wallace V. Crandall;
Joel Rosh ;
James Markowitz;
Michael Stephens;
Richard Kellermayer;
Marian Pfefferkon;
Melvin B. Heyman;
Neal LeLeiko;
David Mack;
Dedrick Moulton;
Michael D. Kappelman;
Archana Kumar;
Jarod Prince;
Promita Bose;
Kajari Mondal;
Dhanya Ramchandran;
John F. Bohnsack;
Anne M. Griffiths ;
Yael Haberman;
Jonah Essers;
Susan D. Thompson;
Bruce Aronow;
David J. Keljo;
Jeffrey S. Hyams;
Lee A. Denson;
Subra Kugathasan
The inflammatory bowel diseases (IBD) are common, complex disorders in which genetic and environmental factors are believed to interact leading to chronic inflammatory responses against the gut microbiota. Earlier genetic studies performed in mostly adult population of European descent identified 163 loci affecting IBD risk, but most have relatively modest effect sizes, and altogether explain only ~20% of the genetic susceptibility. Pediatric onset represents about 25% of overall incident cases in IBD, characterized by distinct disease physiology, course and risks. The goal of this study is to compare the allelic architecture of early onset IBD with adult onset in population of European descent.