Evaluating the Genetic Causes and Progression of Cholestatic Liver Diseases (LOGIC)

• 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 [ Time Frame: Measured at baseline and annually through year 10 ] [ Designated as safety issue: No ]
  

• Jaundice (total serum bilirubin of greater than 2.0 mg/dl) [ Time Frame: Measured at baseline and annually through year 10 ] [ Designated as safety issue: No ]
  
• Listing for liver transplantation [ Time Frame: Measured at baseline and annually through year 10 ] [ Designated as safety issue: No ]
  
• Calculated Pediatric End-Stage Liver Disease (PELD) score for participants less than 12 years of age or Model for End-Stage Liver Disease (MELD) score for participants 12 years of age or older [ Time Frame: Measured at baseline and annually through year 10 ] [ Designated as safety issue: No ]
  
• Health related quality of life [ Time Frame: Measured at baseline and annually through year 10 ] [ Designated as safety issue: No ]
  
• Growth (length and weight Z-score) [ Time Frame: Measured at baseline and annually through year 10 ] [ Designated as safety issue: No ]
  
• Bone mineral density (lumbar and spine total body) [ Time Frame: Measured at baseline in ALGS and PFIC/BRIC subjects ] [ Designated as safety issue: No ]
  
• Presence of hearing loss (ALGS and PFIC) [ Time Frame: Measured at baseline ] [ Designated as safety issue: No ]
  

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— ALGS, 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 10 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 aparticipants 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 (dual energy x-ray absorptiometry, 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 ALGS. Genetic testing will be performed using the collected specimens.