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

• 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 ]

• Jaundice (total serum bilirubin of greater than 2.0 mg/dl) [ Time Frame: Measured at baseline and Years 1, 2, 3, 4, and 5 ] [ Designated as safety issue: No ]
• Listing for liver transplantation [ Time Frame: Measured at baseline and Years 1, 2, 3, 4, and 5 ] [ 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 Years 1, 2, 3, 4, and 5 ] [ Designated as safety issue: No ]
• Health related quality of life [ Time Frame: Measured at baseline and Years 1, 2, 3, 4, and 5 ] [ Designated as safety issue: No ]
• Growth (length and weight Z-score) [ Time Frame: Measured at baseline and Years 1, 2, 3, 4, and 5 ] [ Designated as safety issue: No ]
• Bone mineral density (lumbar and spine total body) [ Time Frame: Measured at baseline and Years 1, 2, 3, 4, and 5 ] [ Designated as safety issue: No ]
• Presence of hearing loss or pancreatic insufficiency (AGS and PFIC) [ Time Frame: Measured at baseline and Years 1, 2, 3, 4, and 5 ] [ Designated as safety issue: No ]

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 (ALGS), alpha-1 antitrypsin (a-1AT) deficiency, bile acid synthesis and metabolism defects, and progressive familial intrahepatic cholestasis (PFIC) or benign recurrent intrahepatic cholestasis(BRIC). 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.

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.

The study population will consist of 400 participants with Alagille syndrome, 400 with alpha-1 trypsin deficieny (of which up to 25 may be siblings of participants), 300 with PFIC (or BRIC), and 50 with bile acid synthesis defects.

• Liver Diseases
• Alagille Syndrome
• Alpha 1-Antitrypsin Deficiency

• 1
  Infants less than 6 months old with a cholestatic liver disease who were initially enrolled into the Childhood Liver Disease Research and Education Network (ChiLDREN) Prospective Biliary Atresia Epidemiology study (PROBE study; P003)
• 2
  Participants with a cholestatic liver disease who are between birth and 25 years old who were NOT initially enrolled into the Childhood Liver Disease Research and Education Network (ChiLDREN) Prospective Biliary Atresia Epidemiology study (PROBE study; P003)
• 3
  Post-liver transplant participants with a cholestatic liver disease who are between 1 day and 25 years old. Affected parents of patients enrolled in the study are eligible for enrollment if they are 25 years old or less
• 4
  A screening group of participants, birth through 25 years old, suspected of having ALGS, PFIC (or BRIC) or BAD, who do not meet complete enrollment criteria for Group 1, 2, or 3.BRIC)
• 5
  Affected siblings (without evidence of liver disease) of Alpha-1 Antitrypsin Deficiency participants who are enrolled in LOGIC.

Inclusion Criteria:

1. Children and young adults diagnosed with one of the four cholestatic diseases from birth through 25 years old.
2. Siblings of participants with alpha-1-antitrypsin deficiency, who themselves have alpha-1-antitrypsin deficiency of liver disease.
3. Both genders, all races and ethnic groups
4. Participant meets the enrollment criteria for one of the four cholestatic liver diseases

Exclusion Criteria:

1. Inability to comply with the longitudinal follow-up described below, or
2. Failure of a family/patient to sign the informed consent document or the HIPAA medical record release form.