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

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 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 (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.

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.