Midwest Children's Consortium

Summary

Principal Investigator: Yumirle P Turmelle
Abstract: The Children's Liver Disease Research and Education Network (ChiLDREN) provides unprecedented opportunities to improve outcomes of pediatric liver diseases worldwide. This proposed Clinical Center submission builds on a strong institutional record in patient enrollment, clinical and bench research, and diagnostic technology at the St. Louis Children's Hospital/Washington University School of Medicine (SLCH/WUSTL) by expanding enrollments to Arkansas Children's Hospital/University of Arkansas for Medical Sciences (ACH/UAMS), interacting with the resources of the Washington University Clinical and Translational Science Award and Queensland Institute for Medical Research, and collaborating with a pediatric primary care network (WU Pediatric/Adolescent Ambulatory Research Consortium). We will apply advanced imaging, pathology, and population analyses to the sophisticated multidisciplinary project required to tackle pediatric liver diseases. Our goals are embodied in the following Specific Aims: Aim I (Clinical Enrollment, Data Accrual, and Specimen (Collection) extends the highly effective SLCH/WUSTL enrollment effort to the active program at ACH/UAMS, generating a large referral base across the central US, that will collect data, sera, pathology samples and sophisticated images from >70 patients annually. We anticipate enhanced contribution to all protocols. Aim 2 (Develop Novel Diagnostic and Prognostic Strategies for ChiLDREN Diseases) tests the hypotheses that identifiable, possibly modifiable mechanisms leading to hepatic fibrosis, and that systematic and rigorous biomarker discovery studies will elucidate these processes, and that competing outcomes and neural network analyses will further define disease course. Aim 3 (Enhance practice quality, and Education) scrutinizes primary care practices and laboratory utilization in an attempt to accelerate identification and referral of infants with cholestasis, focussing on the critical events surrounding presentation, with the goal of defining, then reducing, the factors that hinder timely referral for biliary atresia. Aim 4 (Apply imaging methodologies to ChiLDREN diseases) amalgamates SLCH/WUSTL's advanced liver imaging capabilities to the study of childhood liver diseases, offering these to the Network. These highly matrixed Aims will be built on our enrollment strategies funded by this grant, augmented by existing and anticipated competitive funding, and dedicated WUSTL institutional support. By study conclusion, we intend to generate knowledge that will improve diagnosis, predict outcomes, guide intervention and improve provider practices in ChiLDREN diseases. Relevance: Children with liver disease present major challenges. These diseases are collectively important because of high morbidity, mortality, and public health impact. Management is often ineffective, with cirrhosis, liver failure and liver transplantation as common end-points. Advances in ability to diagnose, and discover causes and determinants of cirrhosis offer hope and potential to impact these outcomes. To achieve this, integration of research and clinical care via a collaborative research consortium is essential.
Funding Period: 2002-09-15 - 2014-05-31
more information: NIH RePORT

Top Publications

  1. ncbi Outcome after portoenterostomy in biliary atresia: pivotal role of degree of liver fibrosis and intensity of stellate cell activation
    Eyal Shteyer
    Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri 63110, USA
    J Pediatr Gastroenterol Nutr 42:93-9. 2006
  2. pmc Health related quality of life in patients with biliary atresia surviving with their native liver
    Shikha S Sundaram
    Departments of Gastroenterology, Hepatology, and Nutrition, Children s Hospital of Colorado, University of Colorado School of Medicine, Aurora, CO Electronic address
    J Pediatr 163:1052-7.e2. 2013
  3. pmc Portal hypertension in children and young adults with biliary atresia
    Benjamin L Shneider
    Children s Hospital Pittsburgh of UPMC, Division of Pediatric Gastoenterology, Hepatology and Nutrition, PA 15224
    J Pediatr Gastroenterol Nutr 55:567-73. 2012
  4. pmc Efficacy of fat-soluble vitamin supplementation in infants with biliary atresia
    Benjamin L Shneider
    Department of Pediatrics, Children s Hospital Pittsburgh of UPMC, Pittsburgh, PA 15224, USA
    Pediatrics 130:e607-14. 2012
  5. pmc Neonatal cholestasis: opportunities to increase early detection
    Joseph J Palermo
    Department of Pediatrics, Washington University, St Louis, MO 63110, USA
    Acad Pediatr 12:283-7. 2012
  6. pmc Pancreatic insufficiency is not a prevalent problem in Alagille syndrome
    Binita M Kamath
    Hospital for Sick Children, Toronto, Canada
    J Pediatr Gastroenterol Nutr 55:612-4. 2012
  7. pmc The anatomic pattern of biliary atresia identified at time of Kasai hepatoportoenterostomy and early postoperative clearance of jaundice are significant predictors of transplant-free survival
    Riccardo Superina
    Children s Memorial Hospital, Chicago, IL, USA
    Ann Surg 254:577-85. 2011
  8. pmc Design and validation of the biliary atresia research consortium histologic assessment system for cholestasis in infancy
    Pierre Russo
    Department of Pathology and Laboratory Medicine, The Children s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
    Clin Gastroenterol Hepatol 9:357-362.e2. 2011
  9. ncbi Fibrogenesis in pediatric cholestatic liver disease: role of taurocholate and hepatocyte-derived monocyte chemotaxis protein-1 in hepatic stellate cell recruitment
    Grant A Ramm
    The Hepatic Fibrosis Group, The Queensland Institute of Medical Research, Brisbane, Australia
    Hepatology 49:533-44. 2009
  10. pmc Growth failure and outcomes in infants with biliary atresia: a report from the Biliary Atresia Research Consortium
    Patricia A DeRusso
    Johns Hopkins School of Medicine and The Johns Hopkins Children s Center, Baltimore, Maryland, USA
    Hepatology 46:1632-8. 2007

Research Grants

  1. North American Mitochondrial Disease Consortium (NAMDC)
    JOHN L THOMPSON; Fiscal Year: 2013
  2. MMC and VICC: Partnership for Survivorship (1 of 2)
    Maureen Sanderson; Fiscal Year: 2013
  3. University of Maryland Greenebaum Cancer Center Support Grant
    Kevin J Cullen; Fiscal Year: 2013
  4. Circulating miRNA as a biomarker for biliary atresia
    Joshua R Friedman; Fiscal Year: 2013
  5. Silvio O. Conte Digestive Diseases Research Core Centers
    Michael H Nathanson; Fiscal Year: 2013
  6. DF/HCC Kidney Cancer SPORE
    David McDermott; Fiscal Year: 2013

Detail Information

Publications14

  1. ncbi Outcome after portoenterostomy in biliary atresia: pivotal role of degree of liver fibrosis and intensity of stellate cell activation
    Eyal Shteyer
    Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri 63110, USA
    J Pediatr Gastroenterol Nutr 42:93-9. 2006
    ..We hypothesized that liver fibrogenesis as determined by intensity of alpha-SMA is already progressing at the time of KP, is related to age and degree of fibrosis at KP, and predicts outcome after KP...
  2. pmc Health related quality of life in patients with biliary atresia surviving with their native liver
    Shikha S Sundaram
    Departments of Gastroenterology, Hepatology, and Nutrition, Children s Hospital of Colorado, University of Colorado School of Medicine, Aurora, CO Electronic address
    J Pediatr 163:1052-7.e2. 2013
    ....
  3. pmc Portal hypertension in children and young adults with biliary atresia
    Benjamin L Shneider
    Children s Hospital Pittsburgh of UPMC, Division of Pediatric Gastoenterology, Hepatology and Nutrition, PA 15224
    J Pediatr Gastroenterol Nutr 55:567-73. 2012
    ..The Childhood Liver Disease Research and Education Network was used to perform a cross-sectional multicentered analysis of PHT in children with BA...
  4. pmc Efficacy of fat-soluble vitamin supplementation in infants with biliary atresia
    Benjamin L Shneider
    Department of Pediatrics, Children s Hospital Pittsburgh of UPMC, Pittsburgh, PA 15224, USA
    Pediatrics 130:e607-14. 2012
    ..In this prospective multicenter study, we assessed the prevalence of FSV deficiency in infants with BA who received this FSV/TPGS preparation...
  5. pmc Neonatal cholestasis: opportunities to increase early detection
    Joseph J Palermo
    Department of Pediatrics, Washington University, St Louis, MO 63110, USA
    Acad Pediatr 12:283-7. 2012
    ..To describe primary care management of early and prolonged jaundice in otherwise-healthy term infants to identify opportunities to increase early diagnosis of cholestasis...
  6. pmc Pancreatic insufficiency is not a prevalent problem in Alagille syndrome
    Binita M Kamath
    Hospital for Sick Children, Toronto, Canada
    J Pediatr Gastroenterol Nutr 55:612-4. 2012
    ..FE measurements were normal (>200  μg/g) in 40 (95%) and indeterminate (100-200  μg/g) in 2 (5%). As FE is the most reliable screen for PI, these data suggest that PI is not a prevalent problem in ALGS...
  7. pmc The anatomic pattern of biliary atresia identified at time of Kasai hepatoportoenterostomy and early postoperative clearance of jaundice are significant predictors of transplant-free survival
    Riccardo Superina
    Children s Memorial Hospital, Chicago, IL, USA
    Ann Surg 254:577-85. 2011
    ..The goals of this study were to describe the clinical and anatomic features of infants undergoing Kasai portoenterostomy (KPE) for biliary atresia (BA) and to examine associations between these parameters and outcomes...
  8. pmc Design and validation of the biliary atresia research consortium histologic assessment system for cholestasis in infancy
    Pierre Russo
    Department of Pathology and Laboratory Medicine, The Children s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
    Clin Gastroenterol Hepatol 9:357-362.e2. 2011
    ....
  9. ncbi Fibrogenesis in pediatric cholestatic liver disease: role of taurocholate and hepatocyte-derived monocyte chemotaxis protein-1 in hepatic stellate cell recruitment
    Grant A Ramm
    The Hepatic Fibrosis Group, The Queensland Institute of Medical Research, Brisbane, Australia
    Hepatology 49:533-44. 2009
    ..In cholestatic rats, increased MCP-1 positively correlated with taurocholate in serum and liver, and negatively correlated in bile. In normal human and rat hepatocytes, taurocholate induced MCP-1 expression...
  10. pmc Growth failure and outcomes in infants with biliary atresia: a report from the Biliary Atresia Research Consortium
    Patricia A DeRusso
    Johns Hopkins School of Medicine and The Johns Hopkins Children s Center, Baltimore, Maryland, USA
    Hepatology 46:1632-8. 2007
    ..The combination of intermediate bilirubin concentrations and poor mean weight z-scores 3 months after HPE was also associated with poor clinical outcome...
  11. ncbi PAI-1 deficiency reduces liver fibrosis after bile duct ligation in mice through activation of tPA
    Hongtao Wang
    Division of Gastroenterology and Nutrition, Department of Pediatrics, Washington University School of Medicine, St Louis, MO 63110, USA
    FEBS Lett 581:3098-104. 2007
    ..In conclusion, PAI-1 deficiency reduces hepatic fibrosis after bile duct obstruction mainly through the activation of tPA and HGF...
  12. ncbi Tissue-type plasminogen activator deficiency exacerbates cholestatic liver injury in mice
    Hongtao Wang
    Division of Gastroenterology and Nutrition, Department of Pediatrics, Washington University School of Medicine, 660 S Euclid Avenue, St Louis, MO 63110, USA
    Hepatology 45:1527-37. 2007
    ..In support of this hypothesis, HGF treatment reverses the effects of tPA deficiency in mice. Furthermore, preferential tPA activation in areas of injury after BDL might occur because fibrin accumulates in bile infarcts and activates tPA...
  13. ncbi A multicenter study of the outcome of biliary atresia in the United States, 1997 to 2000
    Benjamin L Shneider
    Department of Pediatrics, Mount Sinai Medical Center, New York, NY 10029, Department of Biostatistics, University of Michigan, Ann Arbor, MI, and Department of Pediatrics, Children s Hospital of Philadelphia, PA, USA
    J Pediatr 148:467-474. 2006
    ..To determine the prognostic factors and optimal approaches to the diagnosis and management of biliary atresia, the leading indication for liver transplantation in children...
  14. ncbi Use of corticosteroids after hepatoportoenterostomy for bile drainage in infants with biliary atresia: the START randomized clinical trial
    Jorge A Bezerra
    Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio
    JAMA 311:1750-9. 2014
    ..Biliary atresia is the most common cause of end-stage liver disease in children. Controversy exists as to whether use of steroids after hepatoportoenterostomy improves clinical outcome...

Research Grants30

  1. North American Mitochondrial Disease Consortium (NAMDC)
    JOHN L THOMPSON; Fiscal Year: 2013
    ....
  2. MMC and VICC: Partnership for Survivorship (1 of 2)
    Maureen Sanderson; Fiscal Year: 2013
    ..abstract_text> ..
  3. University of Maryland Greenebaum Cancer Center Support Grant
    Kevin J Cullen; Fiscal Year: 2013
    ..Reflecting our remarkable and continued growth, UMGCC seeks to renew its CCSG to enhance and expand its efforts in high-quality and clinically relevant cancer research. ..
  4. Circulating miRNA as a biomarker for biliary atresia
    Joshua R Friedman; Fiscal Year: 2013
    ..It may also lead to insights regarding BA pathogenesis and progress, as well as applications in other liver diseases. ..
  5. Silvio O. Conte Digestive Diseases Research Core Centers
    Michael H Nathanson; Fiscal Year: 2013
    ..A Pilot Feasibility Program supports 1-2 year small grants for new scientific initiatives. The Enrichment Program consists of research seminars, symposia, and retreats. ..
  6. DF/HCC Kidney Cancer SPORE
    David McDermott; Fiscal Year: 2013
    ..The overall goal of the DF/HCC Kidney Cancer SPORE is the translation of biological and technological advances into clinically meaningful advances for patients with kidney cancer. ..