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OUR RESEARCH

 

  • Clinical Studies - This section provides information about ChiLDREN studies. A brief description of each study is provided, with a link to the clinicaltrials.gov website that offers detailed information that may help you consider study participation.
  • Publications and Abstracts - This section provides information on articles and posters prepared and presented at scientific meetings by Network members.

 

 

Clinical Studies

The ChiLDREN Network has several active studies focused on children that are diagnosed with cholestasis:

Most of the ChiLDREN studies are natural history studies aimed at acquiring information and data that will provide a better understanding of these rare conditions.   Participants will be asked to allow study personnel to obtain information from medical records and an interview, and to collect blood, urine, and tissue samples when clinically indicated, in order to understand the causes of these diseases and to improve the diagnosis and treatment of children with these diseases.  All of the information obtained in these studies is confidential and no names or identifying information are used in the study.

Natural History Studies:
PROBE: A prospective study of infants and children with cholestasis.
Eligibility:  Infants up to 6 months of age that have been diagnosed with cholestasis (direct hyperbilirubinemia).
We currently have N/A subjects enrolled in the study.
STUDY ID= NCT00061828

BASIC: A prospective database study of older children with biliary atresia.
Eligibility:  Children and adults age 6 months and older that have been diagnosed with biliary atresia, both before and after liver transplantation.
We currently have N/A subjects enrolled in the study.
STUDY ID= NCT00345553

LOGIC: A longitudinal study of genetic causes of intrahepatic cholestasis.
Eligibility:  Children and adults ages 6 months through 25 years diagnosed with Alagille Syndrome, alpha-1 antitrypsin deficiency, progressive familial intrahepatic cholestasis, or bile acid synthesis defects, both before and after liver transplantation.
We currently have N/A subjects enrolled in the study.

STUDY ID= NCT00571272

MITOHEP: A longitudinal study of mitochondrial hepatopathies.
Eligibility:  Children and adults through age 18 years that have been diagnosed with (or are strongly suspected to have) a mitochondrial liver disease.
We currently have N/A subjects enrolled in the study.
STUDY ID= NCT01148550

PUSH: A longitudinal study of the risk of hepatic cirrhosis in Cystic Fibrosis.
Eligibility: Children ages 3 through 12 years of age with Cystic Fibrosis and pancreatic insufficiency who are enrolled in the CFF or Toronto CF registry studies.
We currently have N/A subjects enrolled in the study. The study is closed to enrollment.

STUDY ID= NCT01144507

Clinical Therapy Trial:
START: A clinical trial to test the efficacy and safety of corticosteroids in the treatment of biliary atresia following hepatic portoenterostomy at a ChiLDREN study site.
Eligibility:  Infants up to 6 months of age that have been diagnosed with biliary atresia and have undergone hepatic portoenterostomy within 72 hours at a ChiLDREN study site.
We currently have 140 subjects enrolled in the study. The study is closed to enrollment.

STUDY ID= NCT00294684

ITCH: A clinical trial to test the efficacy and safety of the Intestinal Bile Acid Transport (IBAT) Inhibitor LUM001 in the treatment of Pruritus in Alagille Syndrome Patients.
Eligibility:  Children and adults between the ages of 2 and 18 years of age that have been diagnosed with Alagille Syndrome and Pruritus.
Study is not yet open for enrollment.
STUDY ID= NCT02057692

PRIME: This is a multi-center open label phase I/IIa clinical trial of high dose IVIG in infants with biliary atresia to determine if the administration of intravenous immunoglobulin (IVIG) in these infants is feasible, well tolerated and safe, to determine if there is a trend towards improved clinical outcomes, and to examine mechanisms that might explain the effects of IVIG in this disease.
Eligibility: Infants up to 4 months of age that have been diagnosed with biliary atresia and have undergone hepatic portoenterostomy within 72 hours at a participating ChiLDREN study site.
We currently have 4 subjects enrolled in the study. The study is actively enrolling.

STUDY ID= NCT01854827

 

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Publications

Manuscripts

  1. Mack CL, Anderson KM, Aubrey MT, Rosenthal P, Sokol RJ and Freed BM. Lack of HLA predominance and HLA shared epitopes in biliary Atresia. SpringerPlus. 2013; 2(1):1-13.

  2. Molleston JP, Sokol RJ, Karnsakul W, Miethke A, Horslen S, Magee JC, Romero R, Squires RH and Van Hove JL for Childhood Liver Disease Research and Education Network. Evaluation of the child with suspected mitochondrial liver disease. J Pediatr Gastroenterol Nutr. 2013; 57(3):269-276.

  3. Schwarz KB, Haber BH, Rosenthal P, Mack CL, Moore J, Bove, K, Bezerra JA, Karpen SJ, Kerkar N, Shneider BL, Turmelle YP, Whitington PF, Molleston JP, Murray KF, Ng VL, Romero R, Wang KS, Sokol RJ and Magee JC for Childhood Liver Disease Research and Education Network. Extra-hepatic anomalies in infants with biliary atresia: results of a large prospective North American multi-center study. Hepatology. 2013 (Epub ahead of print)

  4. Sundaram SS, Alonso EM, Haber B, Magee JC, Fredericks E, Kamath B, Kerkar N, Rosenthal P, Shepherd R, Limbers C, Varni JW, Robuck P and Sokol RJ for Childhood Liver Disease Research and Education Network. Health related Quality of Life in patients with biliary atresia surviving with their native liver. J Pediatr. 2013 (Epub ahead of print).

  5. Brindley SM, Lanham AM, Karrer FM, Tucker RM, Fontenot AP and Mack CL. Cytomegalovirus-specific T-cell reactivity in biliary atresia at the time of diagnosis is associated with deficits in regulatory T cells. Hepatology. 2012; 55(4):1130-1138.

  6. Chu AS, Russo PA and Wells RG. Cholangiocyte cilia are abnormal in syndromic and non-syndromic biliary atresia. Mod Pathol. 2012; 25(5):751-757.

  7. Kamath BM, Bauer RC, Loomes KM, Chao G, Gerfen J, Hutchinson A, Hardikar W, Hirschfield G, Jara P, Krantz ID, Lapunzina P, Leonard L, Ling S, Ng VL, Hoang PL, Piccoli DA and Spinner NB. NOTCH2 mutations in Alagille syndrome. J Med Genet. 2012; 49(2):138-144.

  8. Mack CL, Feldman AG and Sokol RJ. Clues to the etiology of bile duct injury in biliary atresia. Semin Liver Dis. 2012; 32(4):307-316.

  9. Kamath BM, Piccoli DA, Magee JC, and Sokol RJ for Childhood Liver Disease Research and Education Network. Pancreatic insufficiency is not a prevalent problem in Alagille syndrome. J Pediatr Gastroenterol Nutr. 2012; 55(5):612-614.

  10. Penton AL, Leonard LD and Spinner NB. Notch signaling in human development and disease. Semin Cell Dev Biol. 2012; 23(4):450-457.

  11. Sheridan RM, Gupta A, Miethke A, Knisely AS and Bove KE. (Letter to the editor) Multiple dysplastic liver nodules in PFIC2 underscore risk for neoplasia associated with functional BSEP deficiency. Am J Surg Pathol. 2012; 36(5):785-786.

  12. Shneider BL, Abel RB, Haber B, Karpen SJ, Magee JC, Romero R, Schwarz K, Bass LM, Kerkar N, Miethke AG, Rosenthal P, Turmelle Y, Robuck PR and Sokol RJ for Childhood Liver Disease Research and Education Network. Portal hypertension in children and young adults with biliary atresia. J Pediatr Gastroenterol Nutr. 2012; 55(5):567-573.

    Biliary atresia in most circumstances leads to scarring of the liver that may progress to a severe form of scarring referred to as cirrhosis. In the setting of cirrhosis, blood from the intestines and spleen cannot flow through the liver normally and pressure builds up in the blood vessels leading into the liver. This build up of pressure is called portal hypertension. The pressure in these blood vessels is not typically measured directly and therefore clinical findings are used as markers of portal hypertension. Portal hypertension can lead to serious medical problems including bleeding into the intestines, accumulation of fluid in the abdomen, low oxygen levels in blood and build up of toxins. This study looked at portal hypertension in 163 children with biliary atresia who had not had a liver transplant and who were being cared for at centers involved in the Childhood Liver Disease Research and Education Network. The average age of children in this study was 9 years. Portal hypertension was present in about two thirds of the children. Growth was near normal in the children with biliary atresia both with and without portal hypertension. Blood tests were looked at to determine how well the liver functioned. In general liver function was slightly below normal in these children whether they had portal hypertension or not. As would be expected, white blood cell and platelet counts were lower in children with portal hypertension. Overall, children with biliary atresia often have evidence of portal hypertension but are growing well and have a mild reduction in liver function. These children are continuing to be followed by the Childhood Liver Disease Research and Education Network. Future reports will tell us if and when portal hypertension leads to problems for these children.

  13. Shneider BL, Magee JC, Bezerra JA, Haber B, Karpen SJ, Raghunathan T, Rosenthal P, Schwarz K, Suchy FJ, Kerkar N, Turmelle Y, Whitington PF, Robuck PR and Sokol RJ for Childhood Liver Disease Research and Education Network (ChiLDREN). Efficacy of fat soluble vitamin supplementation in infants with biliary atresia: a prospective multi-center analysis. Pediatrics. 2012; 130(3):e607-614.

    Intestinal absorption of fat-soluble vitamins (e.g. vitamins A, D, E and K) is dependent upon the presence of bile acids in the intestine. Infants with biliary atresia may be at risk for fat-soluble vitamin insufficiency due to a potential reduction in bile that is secreted from the liver into the intestine. A multivitamin preparation (ADEKs® or AquADEKs®) that contains a form of vitamin E that is absorbed independent of bile acids is used as a supplement in infants with biliary atresia because it has been presumed to be efficacious. The ChiLDREN consortium prospectively assessed the efficacy of this multivitamin preparation in infants with biliary atresia. Infants with biliary atresia whose total bilirubin was greater than 2 mg/dl in the first 6 months after a Kasai procedure were at high risk of having at least one vitamin insufficiency (either vitamin A, D or E) when standard doses of this multivitamin preparation were utilized. Individual fat-soluble vitamin supplementation and monitoring is necessary to provide optimal fat-soluble vitamin blood levels in infants with biliary atresia who have a total bilirubin greater than 2 mg/dL.

  14. Zahm AM, Hand NJ, Boateng LA and Friedman JR. Circulating microRNA is a biomarker of biliary atresia. J Pediatr Gastroenterol Nutr. 2012; 55(4):366-369.

  15. Bessho K and Bezerra JA. Biliary atresia: will blocking inflammation tame the disease? Annu Rev Med. 2011; 62(X):171-185.

  16. Chu AS, Diaz R, Hui JJ, Yanger K, Zong Y, Alpini G, Stanger BZ and Wells RG. Lineage tracing demonstrates no evidence of cholangiocyte epithelial-to-mesenchymal transition in murine models of hepatic fibrosis. Hepatology. 2011; 53(5):1685-1695.

  17. Evason K, Bove KE, Finegold MJ, Knisely AS, Rhee S, Rosenthal P, Miethke AG, Karpen SJ, Ferrell LD and Kim GE. Morphologic findings in Progressive Familial Intrahepatic Cholestasis 2 (PFIC2): Correlation with genetic and immunohistochemical studies. Am J Surg Path. 2011; 35(5):687-696.

    Twelve children with PFIC2 had light and electron microscopy of liver biopsies as well as genetic evaluation of the BSEP gene, ABCB11.The age at presentation, pace of progressive liver disease and specific genetic mutations were highly varied. Indolent course was noted in two patients with mutations who had demonstrable BSEP in liver canaliculi. Possible linkage was observed between mutations that ended BSEP transcription and severity of hepatocellular injury (necrosis and fibrosis). However, no definitive correlation between specific mutations and histopathology was established in this small series of well-studied patients.

  18. He M, Pei Z, Mohsen AW, Watkins P, Murdoch G, Van Veldhoven PP, Ensenauer R and Vockley J. Identification and characterization of new long chain acyl-CoA dehydrogenases. Mol Genet Metab. 2011; 102(4):418-429.

  19. Li J, Bessho K, Shivakumar P, Mourya R, Mohanty SK, Dos Santos JL, Miura IK, Porta G and Bezerra JA. Th2 signals induce epithelial injury in mice and are compatible with the biliary atresia phenotype. J Clin Invest. 2011; 121(11):4244-4256.

  20. Russo P, Magee JC, Boitnott J, Bove KE, Raghunathan T, Finegold M, Haas J, Jaffe R, Kim GE, Magid M, Melin-Aldana H, White F, Whitington PF, Sokol RJ for the Biliary Atresia Research Consortium. Design and validation of the Biliary Atresia Research Consortium histologic assessment system for cholestasis in infancy. Clin Gastroenterology and Hepatol. 2011; 9(4):357-362.

    The BARC histological assessment system (for studying liver biopsies) identified features of liver biopsies from jaundiced infants, with good agreement between liver pathologists who read the biopsies that might be used in diagnosis and determination of future medical course. The system diagnosed biliary atresia (BA) quite well and identified infants with biliary obstruction with reasonable agreement between pathologists. However, distinguishing between BA and disorders such as total parenteral nutrition associated liver disease and alpha-1-antitrypsin deficiency is not possible without adequate clinical information.

  21. Saxena V, Shivakumar P, Sabla G, Mourya R, Chougnet C and Bezerra JA. Dendritic cells regulate natural killer cell activation and epithelial injury in experimental biliary atresia; *Commentary: McLarnon A. Biliary tract: Dendritic cells activate natural killers in biliary atresia. Nature Rev Gastroenterol Hepatol 2011;8:660. Sci Transl Med. 2011; 3(102):102ra194.

  22. Shin S, Walton G, Aoki R, Brondell K, Schug J, Fox A, Smirnova O, Dorrell C, Erker L, Chu AS, Wells RG, Grompe M, Greenbaum LE and Kaestner KH. Foxl1-Cre-marked adult hepatic progenitors have clonogenic and bilineage differentiation potential. Genes Dev. 2011; 25(11):1185-1192.

  23. Superina R, Magee JC, Brandt ML, Healey PJ, Tiao G, Ryckman F, Karrer FM, Iyer K, Fecteau A, West K, Burns RC, Flake A, Lee H, Lowell JA, Dillon P, Colombani P, Ricketts R, Li Y, Moore J and Wang KS. for Childhood Liver Disease Research and Education Network (ChiLDREN). 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. Ann Surg. 2011; 254(4):577-585.

  24. Leyva-Vega M, Gerfen J, Thiel BD, Jurkiewicz D, Rand EB, Pawlowska J, Kaminska D, Russo P, Gai X, Krantz ID, Kamath BM, Hakonarson H, Haber BA and Spinner NB. Genomic alterations in biliary atresia suggest region of potential disease susceptibility in 2q37.3. Am J Med Genet A. 2010; 152A(4):886-895.

  25. Matte U, Mourya R, Miethke A, Liu C, Kauffmann G, Moyer K, Zhang K and Bezerra JA. Analysis of gene mutations in children with cholestasis of undefined etiology. J Pediatr Gastroenterol Nutr. 2010; 51(4):488-493.

  26. Moyer K, Kaimal V, Pacheco C, Mourya R, Xu H, Shivakumar P, Chakraborty R, Rao M, Magee JC, Bove K, Aronow BJ, Jegga AG and Bezerra JA. Staging of biliary atresia at diagnosis by molecular profiling of the liver. Genome Med. 2010; 2(5):33.

    The investigators analyzed the human genome to determine whether the expression of gene groups can provide insight into the stages of liver disease at the time of diagnosis. To this end, they scored the degree of inflammation and fibrosis (scarring) in the liver biopsies from 47 infants with biliary atresia. They also quantified the expression of all human genes in the liver biopsies using a gene chip. The investigators found that about 1/3 of the patients had either inflammation or fibrosis in the livers at the time of diagnosis using standard anatomical criteria. In contrast, using a new method to classify the patients based on the pattern of gene expression (also known as molecular profiling), they were able to stage the disease into inflammation or fibrosis in a greater percentage of the patients and to link fibrosis with poor outcome. The implication of the findings is that the liver disease of babies with biliary atresia has variable degrees at diagnosis. Future studies will examine whether the use of molecular profiling will aid the monitoring of patients and the design of clinical trials.

  27. Pawlikowska L, Strautnieks S, Jankowska I, Czubkowski P, Emerick K, Antoniou A, Wanty C, Fischler B, Jacquemin E, Wali S, Blanchard S, Nielsen IM, Bourke B, McQuaid S, Lacaille F, Byrne JA, van Eerde AM, Kolho KL, Klomp L, Houwen R, Bacchetti P, Lobritto S, Hupertz V, McClean P, Mieli-Vergani G, Shneider B, Nemeth A, Sokal E, Freimer NB, Knisely AS, Rosenthal P, Whitington PF, Pawlowska J, Thompson RJ and Bull LN. Differences in presentation and progression between severe FIC1 and BSEP deficiencies. J Hepatol. 2010; 53(1):170-178.

  28. Sokol RJ. Reloading against rare liver diseases. J Pediatr Gastroenterol Nutr. 2010; 50(1):9-10.

  29. Van Hove JLK, Saenz MS, Thomas JA, Gallagher RC, Lovell MA, Fenton LZ, Shanske S, Myers SM, Wanders RJ, Ruiter J, Turkenburg M and Waterham HR. Succinyl-CoA ligase deficiency: a mitochondrial hepatoencephalomyopathy. Pediatr Res. 2010; 68(2):159-164.

  30. Wang H, Malone JP, Gilmore PE, Davis AE, Magee JC, Townsend RR and Heuckeroth RO. Serum markers may distinguish biliary atresia from other forms of neonatal cholestasis. J Pediatr Gastroenterol Nutr. 2010; 50(4):411-416.

  31. Griggs RC, Batshaw M, Dunkle M, Gopal-Srivastava R, Kaye E, Krischer J, Nguyen T, Paulus K and Merkel PA. Clinical research for rare disease: opportunities, challenges, and solutions. Mol Genet Metab. 2009; 96(1):20-26.

  32. Sokol RJ. Biliary atresia screening: why, when, and how? Pediatrics. 2009; 123(5):e951-952.

  33. Swigonova Z, Mohsen AW and Vockley J. Acyl-CoA dehydrogenases: Dynamic history of protein family evolution J Mol Evol. 2009; 69(2):176-193.

  34. Strautnieks SS, Byrne JA, Pawlikowska L, Cebecauerova D, Rayner A, Dutton L, Meier Y, Antoniou A, Stieger B, Arnell H, Ozcay F, Al-Hussaini HF, Bassas AF, Verkade HJ, Fischler B, Nemeth A, Kotalova R, Shneider BL, Cielecka-Kuszyk J, McClean P, Whitington PF, Sokal E, Jirsa M, Wali SH, Jankowska I, Pawlowska J, Mieli-Vergani G, Knisely AS, Bull LN and Thompson RJ. Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families. Gastroenterology. 2008; 134(4):1203-1214.

  35. Sundaram SS, Bove KE, Lovell MA and Sokol RJ. Mechanisms of disease: inborn errors of bile acid synthesis. Nat Clin Pract Gastroenterol Hepatol. 2008; 5(8):456-468.

    Bile acids work as natural detergents to help the body break down and use the fats and vitamins taken in as food. They are chemicals made by the liver that start as cholesterol and are converted to their final form through a progressive series of steps. Each step in this path requires a special protein, or enzyme, to occur correctly. An inborn error of bile acid synthesis, an inherited condition, occurs if one of these enzymes is defective. There are 9 known errors of bile acid synthesis, which can cause abnormal liver tests, jaundice, neurologic problems, and severe vitamin deficiencies. If diagnosed early, patients may respond well to medical therapy. This paper carefully reviews the chemical pathway of bile acid synthesis, along with the clinical presentation, diagnosis and treatment of each known error of bile acid synthesis.

  36. DeRusso PA, Ye W, Shepherd R, Haber BA, Shneider BL, Whitington PF, Schwarz KB, Bezerra JA, Rosenthal P, Karpen S, Squires RH, Magee JC, Robuck PR and Sokol RJ. for Biliary Atresia Research Consortium. Growth failure and outcomes in infants with biliary atresia: a report from the Biliary Atresia Research Consortium. J Hepatol. 2007; 46(5):1632-1638.

    Malnutrition is a significant clinical problem in infants with biliary atresia. The natural history of poor growth and its potential association with early need for transplantation or death in children with biliary atresia was determined. Growth velocity was significantly slower in infants with poor bile flow compared to those with good bile flow after the Kasai procedure.

  37. He M, Rutledge SL, Kelly DR, Palmer CA, Murdoch G, Majumder N, Nicholls RD, Pei Z, Watkins PA and Vockley J. A new genetic disorder in mitochondrial fatty acid beta-oxidation: ACAD9 deficiency. Am J Hum Genet. 2007; 81(1):87-103.

  38. Heubi JE, Setchell KD and Bove KE. Inborn errors of bile acid metabolism. Semin Liver Dis. 2007; 27(3):282-294.

  39. Lee WS and Sokol RJ. Liver disease in mitochondrial disorders. Semin Liver Dis. 2007; 27(3):259-273.

  40. Liu C, Aronow BJ, Jegga AG, Wang N, Miethke A, Mourya R and Bezerra JA. Novel resequencing chip customized to diagnose mutations in patients with inherited syndromes of intrahepatic cholestasis. Gastroenterology. 2007; 132(1):119-126.

  41. Mack CL, Falta MT, Sullivan AK, Karrer F, Sokol RJ, Freed BM and Fontenot AP. Oligoclonal expansions of CD4+ and CD8+ T-cells in the target organ of patients with biliary atresia. Gastroenterology. 2007; 133(1):278-287.

  42. Shneider BL, Bezerra JA, Sokol RJ and Whitington PF. Reply to: 'Multicenter Biliary Atresia Outcome Studies: the importance of surgical aspects by Petersen, et. al. J Pediatr. 2007; 150(6):e89-e90.

  43. Sokol RJ, Shepherd RW, Superina R, Bezerra JA, Robuck P and Hoofnagle JH. Screening and outcomes in biliary atresia: summary of a National Institutes of Health workshop. J Hepatol. 2007; 46(2):566-581.

    This report summarizes a National Institutes of Health workshop held on September 12 and 13, 2006 in Bethesda, MD, that addressed the issues of outcomes, screening and pathogenesis of biliary atresia.

  44. Setchell KD and Heubi JE. Defects in bile acid biosynthesis - diagnosis and treatment. J Pediatr Gastroenterol Nutr. 2006; 43(Suppl 1):S17-22.

  45. Shneider BL, Brown MB, Haber B, Whitington PF, Schwarz K, Squires R, Bezerra J, Shepherd R, Rosenthal P, Hoofnagle JH and Sokol RJ. A multicenter study of the outcome of biliary atresia in the United States, 1997 to 2000. J Pediatrics. 2006; 148(4):467-474.

    The objective of the study is to determine the prognostic factors and optimal approaches to the diagnosis and management of biliary atresia, the leading indication for liver transplantation in children. The outcome in the study centers was equivalent to that reported in other countries. Total bilirubin in early follow-up (3 months) after hepatoportoenterostomy was highly predictive of outcome. Efforts to improve bile flow after hepatoportoenterostomy may lead to improved outcome in children with biliary atresia.

  46. Hoofnagle JH. Biliary Atresia Research Consortium (BARC). J Hepatol. 2004; 39(4):891.

  47. Sokol RJ. New North American research network focuses on biliary atresia and neonatal liver disease [News and Views]. J Pediatr Gastroenterol Nutr. 2003; 36(1):1.

    The National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health of the United States (NIDDK) has initiated funding of a 5-year, multicenter study of biliary atresia, neonatal hepatitis, and related neonatal liver diseases.  The overall goal of this consortium is to gather clinical and biochemical data and adequate numbers of serum, tissue and DNA samples in a prospective manner to facilitate research and generate new hypotheses and test existing hypotheses on the pathogenesis and optimal diagnostic and treatment modalities of these disorders.

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Abstracts

  1. Narkewicz MR, Leung D, Molleston JP, Weymann A, Pranjape S, Romero R, Schwarzenberg SJ, Palermo J, Siegel M, Krishnamurthy R, Karmazyn B, Harned R, Ye W and Magee JC for the CFLD Network Group. Later diagnosis and CF related diabetes are associated with abnormal UltraSound (US) in children with CF in the CF Liver Disease Network Study. Presented at 27th Annual North American Cystic Fibrosis Conference (NACFC), Salt Lake City, UT: October 17-19, 2013 (Accepted July 17, 2013).

  2. Dexheimer P, Connor J, Karns R, Miethke A, Aronow B, Zhang K and Bezerra J. High-throughput mutation screen identifies high frequency of double and triple heterozygous gene variants in patients with idiopathic cholestasis. Presented at American Association for the Study of Liver Diseases (AASLD) 63rd Annual Meeting, Boston, MA: November 9-13, 2012. Hepatology 56(S1):204A.

  3. Jericho H, Westfall E, Knisely A, Verkade H and Whitington P. Bile salt kinetics in children with genetic cholestasis and bile diversion therapy. Presented at American Association for the Study of Liver Diseases (AASLD) 63rd Annual Meeting, Boston, MA: November 9-13, 2012. Hepatology 56(S1):208A-209A.

  4. Karjoo S, Hand NJ, Russo P, Friedman J and Wells R. Primary cilia are absent in human biliary remnants and in extra-hepatic ducts of RRV mice. Presented at American Association for the Study of Liver Diseases (AASLD) 63rd Annual Meeting, Boston, MA: November 9-13, 2012. Hepatology 56(S1):723A.

  5. Karjoo S, Pack M, Porter JR and Wells R. A toxin that induces biliary atresia causes disruption of microtubules and loss of primary cilia. Presented at American Association for the Study of Liver Diseases (AASLD) 63rd Annual Meeting, Boston, MA: November 9-13, 2012. Hepatology 56(S1):725A.

  6. Kamath BM, Chen Z, Romero R, Fredericks E and Magee J for the Childhood Liver Disease Research and Education Network. Quality of Life in Alagille syndrome is associated with growth failure and cardiac defects. Presented at American Association for the Study of Liver Diseases (AASLD) 63rd Annual Meeting, Boston, MA: November 9-13, 2012. Hepatology 56(S1):732A-733A.

  7. Molleston J, Sokol RJ, Karsakul WW, Miethke AG, Magee JC, Squires RH, VanHove JL for the Childhood Liver Disease Research and Education Network. Evaluation guidelines for suspected mitochondrial hepatopathies. Presented at World Congress of Pediatric Gastroenterology, Hepatology and Nutrition 4th Annual Meeting, Taipei, Taiwan: November 14-18, 2012.

  8. Molleston J, Sokol RJ, Karsakul WW, Miethke AG, Magee JC, Squires RH, VanHove JL for the Childhood Liver Disease Research and Education Network. Evaluation guidelines for suspected mitochondrial hepatopathies. Presented at North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) 26th Annual Meeting, Salt Lake City, UT: October 18-20, 2012. J Pediatr Gastroenterol Hepatol 55(S1):E112.

  9. Narkewicz MR, Leung DH, Molleston JP, Weymann A, Ling S, Pranjape S, Schwarzenberg SJ, Palermo J, Romero R, Siegel M, Ye W and Magee JC. for the CFLD Network Group. High frequency of unsuspected cirrhosis in children with Cystic Fibrosis (CF). Presented at American Association for the Study of Liver Diseases (AASLD) 63rd Annual Meeting, Boston, MA: November 9-13, 2012. Hepatology 56(S1):205A-206A.

  10. Russo P, Kim G, White F, Bove K, Finegold M, Anders R, Melin-Aldana H, Lovell M, Magid M, Jaffe R, Cummings B, Finn L, Wang L, Shehata B, Spino C and Magee J. for the Childhood Liver Disease Research and Education Network. Key histopathogical features on initial liver biopsy correlate with biliary atresia and outcome post-Kasai. Presented at United States & Canadian Academy of Pathology - Society for Pediatric Pathology (USCAP-SPP) 101st Annual Meeting, Vancouver, BC, Canada: March 17-18, 2012.

  11. Teckman J, Spino C, Murray KF, Haber B, Rudnick DA, Abel R, Thomas DW and Rosenthal P. Baseline analysis of the largest reported cohort of children and young adults with Alpha-1-Antitrypsin deficiency liver disease reveals a significant burden of portal hypertension without jaundice. Presented at Digestive Disease Week (DDW) Annual Meeting, San Diego, CA: May 19-22 2012. Gastroenterol 2012 May; 142(5)(S1):S924.

  12. Bessho K, Mourya R, Dilbone E, Kaimal V, Xu H, Shivakumar P, Rao M, Jegga AG and Bezerra JA. A molecular signature of biliary atresia highly distinct from other cholestatic diseases at diagnosis. Presented at American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting, San Francisco, CA: November 4-8, 2011. Hepatology 2011 Oct; 54(S1):421A.

  13. Clemente AG, Schwarz KB, Patton JT, Yolken RH, Parashar U, Whitington P, Raghunathan T, Jiang B and FoyTich KR. Prevalence of acute asymptomatic group A rotavirus infection in cholestatic infants enrolled in the Biliary Atresia Research Consortium (BARC). Presented at Digestive Disease Week (DDW) Annual Meeting, Chicago, IL: May 7-10, 2011.

  14. Ng VL, Haber B, Magee J, Karpen S, Miethke A, Schwarz K, Shneider B, Whitington P, Turmelle Y, Kerkar N, Rosenthal P, Molleston J, Wang K, Romero R, Murray K, Abel R and Sokol R for the Childhood Liver Disease Research and Education Network. Medical status of 192 children with biliary atresia surviving >5 years after Kasai portoenterostomy with their native liver. Presented at American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting, San Francisco, CA: November 4-8, 2011. Hepatology 2011 Oct; 54(S1):697A-698A.

  15. Shneider BL, Magee JC, Karpen SJ, Rand E, Narkewicz M, Schwarz K, Whitington PF, Bezerra JA, Kerkar N, Haber B, Rosenthal P, Turmelle Y, Molleston J, Murray KF, Ng V, Wang KS, Romero R, Moore J, Robuck PR and Sokol RJ. Prospective multicenter analysis of post-operative total bilirubin as a biomarker for short-term outcome after hepatoportoenterostomy for biliary atresia. Presented at American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting, San Francisco, CA: November 4-8, 2011. Hepatology 2011 Oct; 54(S1):468A.

  16. Zahm A, Hand NJ, Horner A and Friedman J. Serum microRNA is a novel biomarker of biliary atresia. Presented at American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting, San Francisco, CA: November 4-8, 2011. Hepatology 2011 Oct; 54(S1):411A.

  17. Superina R, Magee J, Healey P, Tiao G, Ryckman F, Karrer F, Li Y, Brandt M and Wang KS. 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. Presented at American Surgical Association (ASA) 131st Annual Meeting, Boca Raton, FL: April 14-16, 2011.

  18. Shneider BL, Abel RB, Haber B, Karpen SJ, Magee JC, Romero R, Schwarz KB, Bass LM, Kerkar N, Miethke AG, Rosenthal P, Turmelle YP, and Sokol RJ. Cross-sectional multi-center analysis of portal hypertension in 163 children with biliary atresia. Presented at American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting, Boston, MA: October 29-November 2, 2010. Hepatology 52(S1):347A.

  19. Sokol RJ for Childhood Liver Disease Research and Education Network. Childhood Liver Disease Research and Education Network (ChiLDREN). Presented at American Association for the Study of Liver Diseases (AASLD) 61th Annual Meeting, Boston, MA: October 29-November 2, 2010. Hepatology 52(S1):70A.

  20. Bass LM, Xie H, Yu S, Malladi P, Bento-Soares M and Whitington PF. Metallothionein expression in Progressive Familial Intrahepatic Cholestasis. Presented at American Association for the Study of Liver Diseases (AASLD) 60th Annual Meeting, Boston, MA: October 30-November 3, 2009. Hepatology 2009 Oct; 50(S4):910A-1047A.

  21. Evason K, Bove KE, Knisely AS, Rhee S, Rosenthal P, Miethke A, Ferrell LD and Kim GE. Morphological findings in progressive familial cholestasis 2 (PFIC 2): correlation with genetic and immunohistochemical studies. . Presented at Society for Pediatric Pathology (SPP) 98th Annual Meeting Boston, MA: March 7-8, 2009.

  22. Hahn CL, Sokol RJ and Hines JM for CLiC Patient Advocacy Group Committee. The Patient Advocacy Group Committee of the Cholestatic Liver Disease Consortium: giving families, parents and patients a partnership with researchers. Presented at National Institutes of Health (NIH) Conference “Advancing Rare Diseases Research through Networks and Collaboration” Bethesda, MD: July 16, 2009.

  23. Heubi JE, Setchell KD, Rosenthal P, Shah S, Buckley D, Jha P, Zhang W, Potter CJ, Suskind D and Bull LN. Oral glycocholic acid treatment of patients with Bile acid Amidation Defects improves growth and fat-soluble vitamin absorption. Presented at American Association for the Study of Liver Diseases (AASLD) 60th Annual Meeting, Boston, MA: October 30-November 3, 2009. Hepatology 2009 Oct; 50(S4):895A.

  24. Shneider BL, Abel RB, Raghunathan T, Magee JC, Bezerra JA, Haber B, Karpen SJ, Rosenthal P, Schwarz KB, Shepherd RW, Suchy FJ, Whitington PF, Robuck PR and Sokol RJ. A prospective multi-centered investigation of vitamin supplementation in infants with biliary atresia: interim analysis from the Biliary Atresia Research Consortium (BARC). Presented at American Association for the Study of Liver Diseases (AASLD) 60th Annual Meeting, Boston, MA: October 30-November 3, 2009. Hepatology 2009 Oct; 50(S4):631A-632A.

  25. Sokol RJ and Hines J for CLiC. The Cholestatic Liver Disease Consortium (CLiC): a multi-institutional collaboration to better understand and treat liver disease in children. Presented at National Institutes of Health (NIH) Conference “Advancing Rare Diseases Research through Networks and Collaboration” Bethesda, MD: July 16, 2009.

  26. Sokol RJ, Magee JC, Hahn CL and Robuck PR for Childhood Liver Disease Research and Education Network. The new Childhood Liver Disease Research and Education Network (ChiLDREN): a new cooperative effort between NIDDK, academic centers and Patient Advocacy Groups. Presented at North American Society for Pediatric Gastroenterology, Hepatology And Nutrition (NASPGHAN) Annual Meeting, National Harbor, MD: November 12-14, 2009. J Pediatr Gastroenterol Nutr 2009 Nov; 49(S1):E71.

  27. Sundaram SS, Fredericks EM, Kamath BM, Haber B, Raghunathan T, Magee JC, Bezerra JA, Karpen SJ, Kerkar N, Rosethal P, Schwarz KB, Shepherd RW, Schneider BL, Whitington PF, Robuck PR, Sokol RJ and BARC. Cross sectional assessment of Quality of Life in biliary atresia patients ages 2-25 years. Presented at American Association for the Study of Liver Diseases (AASLD) 60th Annual Meeting, Boston, MA: October 30-November 3, 2009. Hepatology 2009 Oct; 50(S4):632A-633A.

  28. Bass LM, Malladi P and F WP. FXR response in cholestatic liver disease. Presented at American Association for the Study of Liver Diseases (AASLD) 59th Annual Meeting, San Francisco, CA: October 31-November 4, 2008. Hepatology 2008 Oct; 48(S1):668A.

  29. Haber B, Fredericks EM, Magee J, Bezerra JA, Karpen SJ, Kerkar N, Rosenthal P, Schwarz KB, Shepherd RW, Shneider BL, Whitington PF, Robuck PR, Sokol RJ and BARC. Predictors of neurodevelopmental outcome in non-transplanted children with biliary atresia at one year of age. Presented at American Association for the Study of Liver Diseases (AASLD) 59th Annual Meeting, San Francisco, CA: October 31-November 4, 2008. Hepatology 2008 Oct; 48(S1):1028A-1029A.

    Non-transplanted 1 year olds with biliary atresia were significantly below age-based population norms on the Bayley II neurodevelopmental test.  PDI (a test for motor development) was significantly more affected than MDI (a test for intellectual development) and correlated with growth impairment, bilirubin and gestational age, but not with medical complications (ascites, cholangitis, GI bleed).  These data suggest nutritional status plays a role in the etiology of developmental deficits in biliary atresia.

  30. Moyer KD, Kaimal V, Pacheco MC, Mourya R, Xu H, Shivakumar P, Bove KE, Chakraborty R, Rao M, Magee J, Jegga AG and Bezerra JA. Novel molecular subtypes of biliary atresia with relevance to clinical outcome. Presented at American Association for the Study of Liver Diseases (AASLD) 59th Annual Meeting, San Francisco, CA: October 31-November 4, 2008. Hepatology 2008 Oct; 48(S1):371A.

    Livers of infants with biliary atresia  can be assigned inflammatory or fibrosing molecular subtypes, infants with the inflammatory subtype are younger at the time of diagnosis, and the fibrosing subtype is associated with an increased risk of death/liver transplantation within 2 years.  These data suggest that the underlying molecular profile and biology of the liver at diagnosis may be predictive of clinical outcomes in biliary atresia.

  31. Schwarz KB, Shepherd RW, Magee J, Rosenthal P, Mack C, Raghunathan T, Bezerra JA, Haber B, Karpen SJ, Shneider BL, Suchy FJ, Whitington PF, Robuck PR and Sokol RJ. Clinical and demographic features of three major biliary atresia phenotypes in the BARC study. Presented at American Association for the Study of Liver Diseases (AASLD) 59th Annual Meeting, San Francisco, CA: October 31-November 4, 2008. Hepatology 2008 Oct; 48(S1):1028A.

    These findings support that biliary atresia is not a single disease.  The differences in these clinical and epidemiological features in the three  groups according to the clinical presentation suggest that the etiology and pathogenesis of biliary atresia may differ among the three groups.  The three groups include Group I (biliary atresia not associated with major birth defects = 84%), Group II (biliary atresia associated with major birth defects not involving the spleen 9%), and Group III (biliary atresia associated with birth defects involving the spleen 7%). Ongoing studies of BARC (Biliary Atresia Research Consortium) participant specimens and data may help determine the specific causes of these various forms of biliary atresia.

  32. Shneider BL. The Biliary Atresia Research Consortium in the United States of America. Presented at The Taiwan Society for Pediatric Gastroenterology, Hepatology and Nutrition Annual Meeting, Taipei, Taiwan: June 22, 2008.

  33. Matte U, Liu C, Miethke A, Mourya R, Kauffmann G, Moyer K, Bull L, Spinner N, Thompson R and Bezerra J. High throughput sequence analysis identifies individual and combined genetic defects in children with syndromes of intrahepatic cholestasis. Presented at American Association for the Study of Liver Diseases (AASLD) 58th Annual Meeting, Boston, MA: November 2-6, 2007. Hepatology 46(S1):278A.

  34. Miethke A, Matte U, Liu C, Balistreri W, Ryckman F and Bezerra J. Gene mutations and clinical outcome after biliary diversion surgery for intractable pruritus in children with intrahepatic cholestasis. Presented at North American Society for Pediatric Gastroenterology, Hepatology And Nutrition (NASPHAN) Annual Meeting, Salt Lake City, UT: October 25-27, 2007. J Pediatr Gastroenterol Nutr 2007 Oct; 45(S7):E87-E88.

  35. Miethke A, Matte U, Liu C, Mourya R, Ryckman F, Balistreri W, Bove K and Bezerra J. Gene mutations and clinical outcome after biliary diversion surgery for intractable pruritus in children with intrahepatic cholestasis. Presented at Conference on Clinical Research for Rare Diseases: Opportunities, challenges and solutions, Bethesda, MD: September 5 2007.

  36. Shneider B, Shepherd R, Magee J, Bucuvalas JC, Haber B, Karpen SJ, Rosenthal P, Schwarz KB, Suchy FJ, Whitington PF and Sokol RJ. for Biliary Atresia Research Consortium. Discriminating features of biliary atresia - a prospective multi-centered analysis. Presented at American Association for the Study of Liver Diseases (AASLD) 58th Annual Meeting, Boston, MA: November 2-6, 2007. Hepatology 2007 Oct; 46(S1):279A.

    It is difficult to distinguish biliary atresia from other cholestatic liver diseases at the time of presentation on the basis of physical findings and currently utilized routine laboratory parameters.  The combination of acholic stools (chalk white color) and elevated GGT may be the most informative findings.

  37. Russo P, Boitnott J, Bove K, Brown M, Finegold M, Haas J, Jaffe R, Kim G, Magee J, Magid M, Melin-Aldana H, Sokol R, White F for BARC. A multi-institutional study of interobserver agreement on the histologic diagnosis of biliary obstruction in liver biopsies of cholestatic infants less than six months of age. Presented at American Association for the Study of Liver Diseases (AASLD) 57th Annual Meeting, Boston, MA: October 27-31, 2006. Hepatology 2006 Oct; 44(S1):208A.

    A scoring system was developed to help pathologists understand how to diagnose the various causes of jaundice in infancy, particularly biliary atresia. 

  38. Shneider B, Norton K, Superina R, Erlichman J, Magee J, Bucuvalas J, Whitington P, Rosenthal P, Squires R, Benson J, Karpen S, Shepherd R and Sokol R for Biliary Atresia Research Consortium. Diagnostic imaging in neonatal cholestasis: a multi-center prospective analysis. Presented at American Association for the Study of Liver Diseases (AASLD) 57th Annual Meeting, Boston, MA: October 27-31, 2006. Hepatology 2006 Oct; 44(S1):437A.

    Routine clinical application of ultrasonography and hepatobiliary scintigraphy by experienced centers showed a number of misleading results relative to the diagnosis of biliary atresia.  The presence or absence of a gallbladder was not specific for the diagnosis or exclusion of biliary atresia.   Hepatobiliary scans often show no excretion even if biliary atresia is not present.  Exploration with operative cholangiography remain the only definitive means of making the diagnosis of biliary atresia, although caution needs to be exercised in cases of nonvisualization limited to the hepatic ducts.

  39. Sokol RJ, Bezerra J, Haber B, Karpen S, Perlmutter D, Rosenthal P, Schwarz K , Shepherd R, Shneider B, Whitington P, Russo P, Superina R, Magee J, Robuck P and Hoofnagle J for Biliary Atresia Research Consortium. Biliary Atresia Research Consortium (BARC): NIH-funded network to advance knowledge and improve care and outcomes in biliary atresia. Presented at Screening and Outcomes in Biliary Atresia: workshop sponsored by the National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK), Bethesda, MD: September 11-12, 2006.

  40. DeRusso PA, Ye W, Haber B, Shneider BL, Sokol RJ, Whitington PF, Squires RH, Bezerra J, Shepherd R, Rosenthal P and Robuck PR for Biliary Atresia Research Consortium. Early growth failure after portoenterostomy is associated with liver transplantaion or death in infants with biliary atresia. Presented at American Association for the Study of Liver Diseases (AASLD) 56th Annual Meeting, San Francisco, CA: November 11-15, 2005. Hepatology 2005 Oct; 42(S1):222A-223A.

  41. He M, Rutledge SL, Kelly D, Goetzman E and Vockley J. A new defect in beta-oxidation presenting as sudden liver failure. Presented at American Society of Human Genetics (ASHG) 55th Annual Meeting, Salt Lake City, UT: October 25-29, 2005.

  42. He M, Rutledge SL, Kelly DR, Palmer CA, Murdoch G, Majumder N, Nicholls RD, Pei Z, Watkins PA and Vockley J. A new genetic disorder in mitochondrial fatty acid beta-oxidation: ACAD9 deficiency. Presented at International Congress on Inborn Errors of Metabolism, 2005.

  43. He M and Vockley J. New acyl-coA dehydrogenases: redefining long chain fatty acid catabolism in human. Presented at Society for Inherited Metabolic Disorders (SIMD), Pacific Grove, CA: March 5-9, 2005. Molecular Genetics and Metabolism 2005 Mar; 84(3):202-203.

  44. Haber BA, Brown M, Shneider B, Sokol R, Whitington P, DeRusso P, Squires Jr R, Bezerra J, Shepherd R, Rosenthal P, Robuck P and BARC. Patient demographics and clinical practices in a US multi-center study of biliary atresia. Presented at the American Association for the Study of Liver Diseases (AASLD) 55th Annual Meeting, Boston, MA: October 29-November 2, 2004. Hepatology 2004 Oct; 40(S4):472A.

    Birth defects in association with biliary atresia were found in about 20% of infants, more often than in  previous reports.  There was variability between patients with respect to tests performed, use of antibiotics, use of ursodeoxycholic acid and use of steroids.  Age at referral and age at hepatoportoenterostomy continues to be unacceptably high.  Outcome continues to be poor with less than half of patients surviving with their native liver at age 2 years.

  45. Shneider B, Brown M, Sokol R, Whitington P, Schwarz K, Squires R, Bucuvalas J, Haber B, Shepherd R, Rosenthal P, Robuck P, and BARC. A multi-center analysis of outcome at 24 months of age in children with biliary atresia in the United States. Presented at the American Association for the Study of Liver Disease (AASLD) 55th Annual Meeting, Boston, MA: October 29-November 2, 2004. Hepatology 2004 Oct; 40(S4):201A.

 

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Book Sections

  1. Bezerra JA. Biliary atresia. In: Molecular Pathology of Liver Diseases, Monga SPS and Cagle PT (eds.). 1st Ed. Springer: New York, 2011, 753-765.

  2. Rosen H, Sokol RJ and Waasdorp-Hurtado C. Alpha-1 antitrypsin deficiency and other metabolic liver diseases. In: Handbook of Liver Disease, Friedman LS and Keeffe EB (eds.). 3rd Ed. Elsevier: Philadelphia, 2010.

  3. Sokol RJ and Mack CL. Biliary atresia and the ductal plate. In: Gastroenterology: Fibrocystic Diseases of the Liver, Murray KF and Larson AM (eds.). Humana Press: 2010, 179-200.

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