Liver Disease in Urea Cycle Disorders

Sponsor

Baylor College of Medicine (Other)

Overall Status

Recruiting

CT.gov ID

NCT04612764

Collaborator

Children's National Research Institute (Other), Seattle Children's Hospital (Other), Children's Hospital Colorado (Other), Children's Hospital of Philadelphia (Other)

Enrollment

Locations

25.9

Anticipated Duration (Months)

12.4

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a multi-center, cross-sectional study to assess risk for liver fibrosis and hepatic injury in individuals with urea cycle disorders (UCDs) using serum biomarkers, Fibroscan, and MRE. This study will be conducted at 5 sites of the Urea Cycle Disorders Consortium: Baylor College of Medicine in Houston, TX, Seattle Children's Hospital in Seattle, WA, Children's Hospital Colorado in Aurora, CO, Children's Hospital of Philadelphia in Philadelphia, PA, and Children's National Medical Center in Washington D.C.

Condition or Disease	Intervention/Treatment	Phase
Urea Cycle Disorder Ornithine Transcarbamylase Deficiency Citrullinemia 1 ARGI Deficiency ASL Deficiency Argininosuccinic Aciduria ASS Deficiency Hyperargininemia

Detailed Description

Urea cycle disorders (UCDs) are among the most common inborn errors of liver metabolism. With early diagnosis and improved treatments, the survival of individuals with UCDs has improved, and this improved survival has led to unmasking of some long-term complications such as hepatic dysfunction and progressive fibrosis in a subset of patients. Hepatic complications in UCDs are quite variable and dependent upon the specific metabolic defect.

Currently, there are no guidelines for monitoring hepatic complications or extent of liver disease in UCDs. The gold standard for staging of fibrosis or confirming cirrhosis has traditionally been liver biopsy, an invasive procedure with inherent risks, particularly in the setting of a UCD and compromised coagulation. Recently, non-invasive serum and imaging-based biomarkers have been introduced to assess hepatic fibrosis in adults and children who are at increased risk. Utilization of these technique in individuals with UCDs could be invaluable in both the research and clinical arenas.

The purpose of this study is:

To assess risk for increased fibrosis using serum biomarkers and/or VCTE in distal disorders (ASS1D, ASLD and ARG1D) as compared to OTCD 2 ) To assess risk for hepatic fibrosis (liver stiffness as measured by MRE) in individuals with UCDs who have abnormal serum biomarkers and/or VCTE as those who have normal values

Study Design

Study Type:

Observational

Anticipated Enrollment :

62 participants

Observational Model:

Other

Time Perspective:

Cross-Sectional

Official Title:

Noninvasive Biomarkers of Hepatic Fibrosis in Urea Cycle Disorders

Actual Study Start Date :

Nov 4, 2021

Anticipated Primary Completion Date :

Dec 31, 2023

Anticipated Study Completion Date :

Dec 31, 2023

Outcome Measures

Primary Outcome Measures

Fibrotest [One measurement made on the 1 day of the study visit (stage A)]
Fibrotest(TM)
Fibroscan (liver stiffness) [One measurement made on the 1 day of the study visit (stage A)]
Liver stiffness (kPa) as assessed by Fibroscan®
Fibroscan (CAP) [One measurement made on the 1 day of the study visit (stage A)]
Controlled Attenuation Parameter (CAPTM in dB/m) as assessed by Fibroscan®
MRE [One measurement made on the 1 day of the study visit (stage B)]
Liver stiffness (kPa) as measured by MRE

Secondary Outcome Measures

Albumin [One measurement made on the 1 day of the study visit (stage A)]
Albumin
Liver Enzymes [One measurement made on the 1 day of the study visit (Stage A)]
Aspartate aminotransferase, Alanine aminotransaminase, and Gamma glutamyl transferase
Total Bilirubin [One measurement made on the 1 day of the study visit (stage A)]
Total Bilirubin
Prothrombin time [One measurement made on the 1 day of the study visit (stage A)]
Prothrombin time
INR [One measurement made on the 1 day of the study visit (stage A)]
INR
AST-to-Platelet Ratio (APRI) [One measurement made on the 1 day of the study visit (stage A)]
AST-to-Platelet Ratio (APRI)
GGT-to-Platelet Ratio (GPR) [One measurement made on the 1 day of the study visit (stage A)]
GGT-to-Platelet Ratio (GPR)
Fibrosis-4 (FIB-4) Index [One measurement made on the 1 day of the study visit (stage A)]
Fibrosis-4 (FIB-4) Index
MRE [One measurement made on the 1 day of the study visit (stage B)]
Fat fraction (%) as measured by MRE

Eligibility Criteria

Criteria

Ages Eligible for Study:

6 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Stage A

Inclusion Criteria:

Age > 6 years and < 65 years
Weight ≥ 11 kg at time of screening
A molecular or biochemical diagnosis of OTCD, ASS1D, ASLD, or ARG1D.

Exclusion Criteria:

Prior liver transplantation
Episode of acute hyperammonemia (≥100 umol/L) in the 30 days prior to enrollment
Confirmed diagnosis of chronic viral hepatitis, autoimmune liver disease, short gut, small bowel syndrome, alcohol liver disease, TPN requirement, or TPN-related cholestatic disease
Adults with BMI ≥ 45 kg/m2
Current pregnancy
Open wound near expected Fibroscan® probe application site
Use of implantable active medical device such as cardiac pacemaker or implantable cardioverter-defibrillator

Stage B Inclusion Criteria

• Participation in Stage A of this study

Exclusion Criteria

Individuals with claustrophobia or other inability to complete
Known diagnosis of hemochromatosis
Presence of implants or devices incompatible with MRI
Inability to breath-hold for 20 seconds for the elastography sequence
Current pregnancy
Confirmed diagnosis of chronic viral hepatitis, autoimmune liver disease, short gut, small bowel syndrome, alcohol liver disease, TPN requirement, or TPN-related cholestatic disease
Episode of documented acute hyperammonemia (ammonia ≥ 100 umol/L) in the 30 days prior to scheduled visit for Stage B

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital Colorado	Aurora	Colorado	United States	80045
2	Children's National Medical Center	Washington	District of Columbia	United States	20010
3	The Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
4	Baylor College of Medicine	Houston	Texas	United States	77030
5	Seattle Children's Hospital	Seattle	Washington	United States	98105