Liver-Related Work

I am actively involved in two NIH/NIDDK funded consortia studying pediatric liver diseases. I am the site Principal Investigator for the Childhood Liver Disease and Research Network (ChiLDReN), which represents 13 enrolling sites in the United States and Canada, four core laboratory sites for histopathology, bile acid biochemistry, genetics, and respiratory chain analysis, an NIH funded
biorepository, one data coordinating center, and is associated with eight patient and family advocacy groups, including the American Liver Foundation and the United Mitochondrial Disease Foundation.

I am also Principal Investigator for the Pediatric Acute Liver Failure Study Group (PALFSG). Having received 15 years of continuous funding, the PALFSG is now in a no-cost extension period of data analysis.
We established a trans-disciplinary collaboration to ensure a structured diagnostic and management strategy, to monitor clinical, biochemical, and physiological parameters, and to collect markers of the immune
and inflammatory milieu, neurological injury, and liver regeneration. The PALFSG initially included 24 sites (21 in the United States, two in the United Kingdom, and one in Canada) with established expertise in
pediatric liver disease and transplantation. The current clinical network consists of 12 sites in North America in addition to the Data Coordinating Center at the University of Pittsburgh.

• ChiLDReN: Biliary atresia study in infants, children, and adults. This is a prospective longitudinal study of children older than 6 months of age with biliary atresia. Gene(s) implicated in the etiology of BA, polymorphisms underlying disease progression, and the natural history of biliary atresia will be studied. Research visits take place annually for up to 10 years for children with their native liver. Children with BA who have had liver transplant will be enrolled for one visit only for collection of data and blood for DNA. In addition, a biobank of patient specimens and DNA samples have been established for use in ancillary studies to be performed in addition to this study.
• ChiLDReN: A prospective database of infants with cholestasis. This is a prospective longitudinal study of neonatal cholestasis with the following objectives:
  1. Establish a national database of demographic and clinical information, as well as a repository for bio-specimens of infants with cholestatic disease and their families.
  2. The database will provide a means of following these children over time to characterize the natural history of the disease and to identify environmental, infectious, and genetic risk factors related to onset, outcome, and treatment success for the different cholestatic diseases, with special emphasis on biliary atresia.
  3. Subjects are followed for up to 15 years after enrollment.
• ChiLDReN: Longitudinal study of genetic causes of intrahepatic cholestasis. This is a multicenter longitudinal observational study investigating the natural history and progression of four genetic causes of intrahepatic cholestasis of childhood, including: alpha-1 antitrypsin deficiency, Alagille syndrome (ALGS), Progressive familial intrahepatic cholestasis (PFIC) or benign recurrent intrahepatic cholestasis (BRIC), and bile acid synthesis defects (BAD).
• ChiLDReN: Longitudinal study of mitochondrial hepatopathies. This study is a multicenter longitudinal cohort study of patients with mitochondrial hepatopathies. The focus is on respiratory chain defects (RC) and defects of fatty acid oxidation (FAO). Each subject’s participation in this research study will be a maximum of 10 years.
• ChiLDReN: Evaluation of the intestinal bile acid transport (IBAT) inhibitor LUM001 in the reduction of pruritus in Alagille syndrome, a cholestatic liver disease (ITCH). This is a multicenter trial involving children and young adults with Alagille Syndrome. The study is designed to investigate the effects of LUM001, compared to placebo, on pruritis, serum bile acids, liver enzymes, and other biochemical markers associated with cholestatic liver disease.
• ChiLDReN: A Multicenter Extension Study to Evaluate the Long-Term Safety and Durability of the Therapeutic Effect of LUM001, an Apical Sodium-Dependent Bile Acid Transporter Inhibitor (ASBTi), in the Treatment of Cholestatic Liver Disease in Pediatric Subjects with Alagille Syndrome (IMAGINE). This is a multicenter, double-blind study of LUM001 in children older than 12 months of age diagnosed with ALGS who have completed participation in the LUM001-301 protocol. All subjects will receive active drug (LUM001) in the study. The study is divided into three parts:
  1. a dose escalation period,
  2. a dose optimization period, and
  3. a stable dosing period.
  Planned participation for each subject enrolled in the study is 48 weeks.
• A Preliminary Study of the Efficacy and Safety of Carbamazepine in Severe Liver Disease Due to Alpha-1-Antitrypsin Deficiency. This is a phase II prospective study of the use of CBZ in adolescents and adults with AT deficiency and compensated cirrhosis. Design: randomized, double-blinded, placebo-controlled study in which 20 subjects will receive drug and 10 subjects will receive placebo. Duration: Eligible subjects will take CBZ or placebo for 12 months. Procedure: Transvenous catheterization of the hepatic vein for measurement of hepatic venous pressure gradient will be carried out before and after the treatment period. Liver biopsies will be carried out at the same time to obtain liver tissue for measurement of hepatic ATZ load and hepatic fibrosis.
• Site Protocol for Ursodeoxycholic Acid Therapy in Pediatric Primary Sclerosing Cholangitis: A Pilot Withdrawal/Reinstitution Trial (WUP-SC). A multicenter, preliminary UDCA withdrawal and reinstitution trial in pediatric PSC patients to collect data to support the design of a larger, longer-term randomized, placebo controlled trial of UDCA therapy in childhood PSC. In addition to liver biochemical markers, biomarkers for liver and biliary inflammation will also be examined.
• Studies of Primary Sclerosing Cholangitis (STOPSC). The study is a collaborative effort among centers in the United States and Canada to collect and analyze information required to understand the etiology, pathogenesis, and treatment of PSC. Functions as the Database for WUP-PSC.
• Research Registry Protocol for Byler Disease. This research registry will collect both retrospective and prospective data on patients with Byler Disease seen in the Department of Gastroenterology, Hepatology, and Nutrition at Children’s Hospital of Pittsburgh of UPMC, which will advance our understanding of this disease and may serve as a historical control for future clinical trials involving this disease.
• Expanded Access Protocol for an Intermediate Size Population RAVICTI for Byler Disease, PRO13110219. (suspended) Plan on reopening in next few months.
• Observational Study of Children with Acute Liver Failure in North America (PALF) PRO11110681. Open for data collection on active subjects and data analysis. Closed to enrollment.
• Neurocognitive Function and Health Quality of Life in Pediatric Survivors of Acute Liver Failure.

• Yoram Vodovotz, PhD and Rubin Zamora, PhD – Evaluation of immune and inflammatory networks, using in vivo, in vitro, and in silico techniques, in pediatric acute liver failure.
• Mike Bell, MD – Non-invasive biomarkers of brain injury in pediatric acute liver failure.
• Mark Roberts, MD, Cindy Bryce, and Joyce Chang – Develop models to optimize clinical decisions in individual children who require liver transplantation that aggregates multiple transplantation-related decisions into a representation of the entire US organ allocation system.
• Lans Taylor, PhD, Alex Soto-Gutierrez, MD, PhD, and Charleen Chu, MD, PhD – Liver chip technology and cholestatic liver diseases in children.

Professor
Department of Pediatrics