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

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.

Study Overview

• Status: Suspended
• Conditions: Liver Diseases; Alpha 1-Antitrypsin Deficiency; Alagille Syndrome

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- 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.

Participants who have been previously enrolled into this study will be followed for 20 years, until transplanted, or death. 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.

• Study Type: Observational
• Enrollment (Estimated): 1675

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • The Hospital for Sick Children
• United States
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital of Los Angeles
    • San Francisco, California, United States, 94143
      • University of California at San Francisco (UCSF)
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta - Emory University
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert H. Lurie Children's Hospital of Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University Hospital
  • Missouri
    • St Louis, Missouri, United States, 63104
      • St. Louis University - Cardinal Glennon Children's Medical Center
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine/St. Louis Children's Hospital
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine
  • Ohio
    • Cincinnati, Ohio, United States, 60190
      • Cincinnati's Children's Memorial Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • UPMC Children's Hospital of Pittsburgh
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor School of Medicine
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • University of Utah
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 25 years (Child, Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

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.

Description

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 are affected with alpha-1-antitrypsin deficiency, but have no evidence of liver disease.
3. Both sexes, all races and ethnic groups.
4. Participant meets the enrollment criteria for one of the four cholestatic liver diseases.
5. 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.

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
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
5; Affected siblings (without evidence of liver disease) of Alpha-1 Antitrypsin Deficiency participants who are enrolled in LOGIC.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Arbor Research Collaborative for Health
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Study Director: Ed Doo, MD, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Study Chair: Kathleen Loomes, MD, Children's Hospital of Philadelphia; Principal Investigator: John Magee, MD, University of Michigan; Principal Investigator: Lisa Henn, PhD, Arbor Research Collaborative for Health; Study Director: Katrina Loh, MD, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Publications and helpful links

General Publications

• Leung DH, Sorensen LG, Ye W, Hawthorne K, Ng VL, Loomes KM, Fredericks EM, Alonso EM, Heubi JE, Horslen SP, Karpen SJ, Molleston JP, Rosenthal P, Sokol RJ, Squires RH, Wang KS, Kamath BM, Magee JC; Childhood Liver Disease Research Network (ChiLDReN). Neurodevelopmental Outcomes in Children With Inherited Liver Disease and Native Liver. J Pediatr Gastroenterol Nutr. 2022 Jan 1;74(1):96-103. doi: 10.1097/MPG.0000000000003337.
• Teckman JH, Rosenthal P, Abel R, Bass LM, Michail S, Murray KF, Rudnick DA, Thomas DW, Spino C, Arnon R, Hertel PM, Heubi J, Kamath BM, Karnsakul W, Loomes KM, Magee JC, Molleston JP, Romero R, Shneider BL, Sherker AH, Sokol RJ; Childhood Liver Disease Research Network (ChiLDReN). Baseline Analysis of a Young alpha-1-Antitrypsin Deficiency Liver Disease Cohort Reveals Frequent Portal Hypertension. J Pediatr Gastroenterol Nutr. 2015 Jul;61(1):94-101. doi: 10.1097/MPG.0000000000000753.
• Teckman J, Rosenthal P, Ignacio RV, Spino C, Bass LM, Horslen S, Wang K, Magee JC, Karpen S, Asai A, Molleston JP, Squires RH, Kamath BM, Guthery SL, Loomes KM, Shneider BL, Sokol RJ; ChiLDReN (Childhood Liver Disease Research Network). Neonatal cholestasis in children with Alpha-1-AT deficiency is a risk for earlier severe liver disease with male predominance. Hepatol Commun. 2023 Dec 7;7(12):e0345. doi: 10.1097/HC9.0000000000000345. eCollection 2023 Dec 1.

Helpful Links

• Childhood Liver Disease Research Network (ChiLDReN) website

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2007
• Primary Completion (Estimated): May 31, 2029
• Study Completion (Estimated): May 31, 2029

Study Registration Dates

• First Submitted: December 7, 2007
• First Submitted That Met QC Criteria: December 7, 2007
• First Posted (Estimated): December 11, 2007

Study Record Updates

• Last Update Posted (Actual): June 4, 2026
• Last Update Submitted That Met QC Criteria: June 3, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Genetic Diseases; Cholestasis; Cholestatic Liver Disease; Childhood Diseases; Bile Acid Synthesis and Metabolism Defects; Progressive Familial Intrahepatic Cholestasis
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Pathologic Processes; Respiratory Tract Diseases; Digestive System Diseases; Lung Diseases; Biliary Tract Diseases; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Defects, Congenital; Abnormalities, Multiple; Bile Duct Diseases; Subcutaneous Emphysema; Emphysema; Cholestasis, Intrahepatic; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Genetic Diseases, Inborn; Liver Diseases; Cholestasis; Alagille Syndrome; alpha 1-Antitrypsin Deficiency; Cholestasis, progressive familial intrahepatic 1
• Other Study ID Numbers: LOGIC Study - ChiLDReN Network; U01DK062436 (U.S. NIH Grant/Contract); U01DK062456 (U.S. NIH Grant/Contract); U01DK103149 (U.S. NIH Grant/Contract); U01DK103140 (U.S. NIH Grant/Contract); U01DK103135 (U.S. NIH Grant/Contract); U01DK084575 (U.S. NIH Grant/Contract); U01DK084538 (U.S. NIH Grant/Contract); U01DK084536 (U.S. NIH Grant/Contract); U01DK062503 (U.S. NIH Grant/Contract); U01DK062500 (U.S. NIH Grant/Contract); U01DK062497 (U.S. NIH Grant/Contract); U01DK062481 (U.S. NIH Grant/Contract); U01DK062470 (U.S. NIH Grant/Contract); U01DK062466 (U.S. NIH Grant/Contract); U01DK062453 (U.S. NIH Grant/Contract); U01DK062452 (U.S. NIH Grant/Contract); U01DK062445 (U.S. NIH Grant/Contract); U24DK062456 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The data will be transferred to NIDDK at the end of the study.

Drug and device information, study documents

• product manufactured in and exported from the U.S.: No