Diseases

Evaluating the Genetic Causes and Progression of Cholestatic Liver Diseases

Descriptive Information
Brief Title ^†	Evaluating the Genetic Causes and Progression of Cholestatic Liver Diseases
Official Title ^†	Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis
Brief Summary	Cholestasis is a condition in which bile is not properly transported from the liver to the small intestine. Cholestasis can be caused by an array of childhood diseases, including the genetic diseases Alagille syndrome (AGS), alpha-1 antitrypsin (a-1AT) deficiency, bile acid synthesis and metabolism defects, and progressive familial intrahepatic cholestasis (PFIC). This study will investigate the natural history and progression of the four previously mentioned cholestatic liver diseases to provide a better understanding of the causes and effects of the diseases.
Detailed Description	Cholestasis is a rare condition that involves a reduction or obstruction of bile flow from the liver to the small intestine. When bile flow is hindered, a waste product pigment called bilirubin can escape into the bloodstream and build up to harmful levels. This may lead to the easily recognizable cholestatic symptoms of jaundice, itching, and impaired growth and eventually to more serious health problems. Four rare genetic liver disorders— AGS, a-1AT, bile acid synthesis and metabolism defects, and PFIC—account for about 20% to 30% of all infant cases of cholestasis. These four disorders compose a group of related diseases that can cause significant growth problems during childhood, serious liver problems, the need for liver transplantation, and potentially death. More research on these rare liver diseases is necessary to develop a scientific basis for improvement in diagnostic techniques and treatments. Current diagnostic procedures are complex, and the development of simpler diagnostic tests would facilitate early diagnosis and treatment. This study will investigate the natural history and progression of the four previously mentioned cholestatic liver diseases to provide a better understanding of the causes and effects of the diseases. Participation in this study will last 5 years and will consist of a baseline visit and five annual follow-up visits. The study will enroll infants through adults 25 years of age who have, or are suspected of having, one of the four genetic cholestatic liver diseases. Individuals who are siblings of a-A1T and AGS participants and have underlying disease with no evidence of liver involvement may also be enrolled. Study visits will involve review of clinical information, family history, and any clinically indicated treatments and their outcomes; a physical exam; laboratory tests; and radiologic and imaging evaluations. In addition to these standard of care evaluations, participants will undergo several special research evaluations, including quality of life questionnaires, neurodevelopmental evaluations, hearing exams, DEXA scanning, liver histology studies, and collection of serum, plasma, urine, and blood for DNA or cell lines. Serum, plasma, urine, and blood for DNA or cell lines will also be collected from both biological parents and from affected siblings of participants with a-A1T or AGS. Genetic testing will be performed using the collected specimens.
Study Phase	N/A
Study Type ^†	Observational
Study Design ^†	Observational Model: Cohort, Time Perspective: Prospective
Primary Outcome Measure ^†	Demonstration of disease progression for each of the four cholestatic liver diseases of the study, including liver transplantation, death, growth failure, worsening liver function, and developmental complications of portal high blood pressure
Secondary Outcome Measure ^†	Jaundice (total serum bilirubin of greater than 2.0 mg/dl)
Condition ^†	Liver Diseases Alagille Syndrome Alpha 1-Antitrypsin Deficiency
Intervention ^†
Study Arms / Comparison Groups	1 Infants less than 6 months old with a cholestatic liver disease who were initially enrolled into the Biliary Atresia Clincal Research Consortium (BARC) Prospective Biliary Atresia Epidemiology study (PROBE study; P003) 2 Participants with a cholestatic liver disease who are between 6 months and 25 years old 3 Post-liver transplant participants with a cholestatic liver disease who are between 1 day and 25 years old 4 Participants undergoing screening enrollment for a cholestatic liver disease 5 Affected siblings of participants with alpha-1 antitrypsin deficiency (a-1AT) or Alagille Syndrome (AGS)
Publications *
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status ^†
Estimated Enrollment ^†	590
Start Date ^†	November 2007
Completion Date	June 2013
Primary Completion Date	June 2013
Eligibility Criteria ^†	Inclusion Criteria: Meets criteria for or previously diagnosed with one of four cholestatic liver diseases: AGS, a-1AT, bile acid synthesis and metabolism defects, or PFIC Siblings of participant with AGS or a-1AT, who may themselves have the underlying disease but without liver involvement Literate in English Ability to complete an annual research visit at one of the participating Cholestatic Liver Disease Consortium (CLiC) centers Specific Exclusion Criteria for PFIC Participants: Confirmed diagnosis of cholestatic liver disease other than the four from this study Short bowel syndrome/total parenteral nutrition (TPN) related disease Chronic known infectious hepatitis (e.g, hepatitis C, hepatitis B, etc.) Acquired immunodeficiency syndrome (AIDS) Chronic known or strongly suspected drug toxicity (e.g., augmentin related cholestasis) Acute liver failure Extrahepatic portal vein obstruction, congenital hepatic fibrosis, or congential portosystemic shunt Specific Exclusion Criteria for Bile Acid Synthesis and Metabolism Defects Participants: Peroxisomal enzyme or structural defect producing a recognized syndromic disorder, such as Zellweger syndrome, Refsum's syndrome, neonatal adrenoleukodystrophy, or Smith-Lemni-Opitz syndrome
Gender	Both
Ages	N/A - 25 Years
Accepts Healthy Volunteers	No
Contacts ^††	Elizabeth Esterl, RN, MS, CCRC, 720-777-8430, esterl.elizabeth@tchden.org , ,
Location Countries ^†	United States,
Administrative Information
NCT ID ^†	NCT00571272
Organization ID	RDCRN 6001
Secondary IDs ^††
Responsible Party	Ronald J. Sokol, MD, University of Colorado Denver School of Medicine
Study Sponsor ^†	Office of Rare Diseases (ORD)
Collaborators ^††	Rare Diseases Clinical Research Network National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators ^†	Study Chair: Ronald J. Sokol, MD, University of Colorado, Denver
Information Provided By	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Verification Date	December 2010
First Received Date ^†	December 7, 2007
Last Updated Date	December 6, 2010

^† Required WHO trial registration data element.
^†† WHO trial registration data element that is required only if it exists.