Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC)

Study Overview
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Brief Summary
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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.

Detailed Description
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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 20 years and will consist of a baseline visit and 20 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, liver histology studies, and collection of serum, plasma, urine, and blood for DNA. Serum, plasma, and blood for DNA 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.

Official Title
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Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC)

Conditions
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Liver Diseases, Alagille Syndrome, Alpha 1-Antitrypsin Deficiency

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children and young adults diagnosed with one of the four cholestatic diseases from birth through 25 years old. Siblings of participants with alpha-1-antitrypsin deficiency, who are affected with alpha-1-antitrypsin deficiency, but have no evidence of liver disease. Both sexes, all races and ethnic groups. Participant meets the enrollment criteria for one of the four cholestatic liver diseases. Patient and/or parent/legal guardian have the ability to provide written informed consent for enrollment. Exclusion Criteria: 1. Inability to comply with the longitudinal follow-up described in the protocol.

Ages Eligible for Study
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Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| 1<br>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<br>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<br>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<br>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<br>Affected siblings (without evidence of liver disease) of Alpha-1 Antitrypsin Deficiency participants who are enrolled in LOGIC. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |  | Measured at baseline and annually through year 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Jaundice (total serum bilirubin of greater than 2.0 mg/dl) |  | Measured at baseline and annually through year 10 | 
| Listing for liver transplantation |  | Measured at baseline and annually through year 10 | 
| 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 |  | Measured at baseline and annually through year 10 | 
| Health related quality of life |  | Measured at baseline and annually through year 10 | 
| Growth (length and weight Z-score) |  | Measured at baseline and annually through year 10 | 
| Bone mineral density (lumbar and spine total body) |  | Measured at baseline in ALGS and PFIC/BRIC subjects | 
| Presence of hearing loss (ALGS and PFIC) |  | Measured at baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cholestasis, Cholestatic Liver Disease, Childhood Diseases, Genetic Diseases, Bile Acid Synthesis and Metabolism Defects, Progressive Familial Intrahepatic Cholestasis